Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition. We thus conclude that the need to study spina bifida in all its forms, both aperta and occulta, is more indicative of the spina bifida in surviving humans and that the measure of deterioration arising from caudal neural tube defects, more commonly known as spina bifida, must be determined by the level of the lesion both in mouse and in man.
Universiti MalayaUM.C/625/1/HIR/062–J-20011-73595UM.C/625/1/HIR/148/2–J-20011-73843PPP PG153-2015AMinistry of Higher Education MalaysiaUM.C/625/1/HIR/MOHE/MED/08/04–E-0000321. Introduction
Spina bifida is the most common and complex central nervous system malformation in humans. Management of these patients involves various disciplines to ensure the best possible outcome achieved and provide a good quality of life for its patients [1, 2]. The study of this condition is extremely relevant in that even in the 20 years since the discovery of the benefits of folic acid this condition is highly prevalent around the world and its occurrence does not seem to decrease [3]. Interestingly, the debate is very much ongoing upon the evidence that the United States of America has seen a decline in cases of spina bifida (https://www.cdc.gov/ncbddd/spinabifidadata.html). This review paper intends to compare and contrast spina bifida in humans and spina bifida in the mouse, which is the leading animal model of this devastating condition in light of the information studies on animal models have shed on the human counterpart [4–6].
2. Spina Bifida in Humans
Development of the central nervous system including the brain and spinal cord is a complex process beginning with a flat sheet of cells which undergoes sequential thickening, elevation, mediolateral convergence accompanied by rostrocaudal extension, and finally adhesion to form the neural tube (NT) which is the precursor of the brain and the spinal cord. Perturbations of these interconnected processes result in neural tube defects (NTDs), which are the most common congenital malformation affecting this system and are associated with significant complications. NTDs can occur in two major forms: spina bifida (SB) aperta, which is the open-lesion NTD, and the closed-lesion NTD, more commonly known as SB occulta.
3. Epidemiology
Spina bifida is the most common nonlethal malformation in the spectrum of NTDs and has an incidence generally around 0.5 per 1,000 births, although higher frequencies have been reported [7–11]. In the United Kingdom, the population prevalence of spina bifida is 7.8–8.4 per 10,000 for males and 9.0–9.4 per 10,000 for females [12]. While the prevalence in the United States of America is more than 3 in every 10,000 births [8, 13], studies in parts of Asia, such as Malaysia, have also shown a lower occurrence of spina bifida than that of the UK [14]. More recent efforts by our group (“Spina Bifida: A 10-Year Retrospective Study at University of Malaya Medical Centre, Malaysia,” manuscript in submission), however, have found that the lower rate of NTDs may not be completely representative as in our hospital alone from the years 2003 to 2012 we have had over 10 cases of neural tube defects per year (spina bifida and anencephaly). Furthermore, certain regions of China have shown much higher preponderance of this condition than in other parts of the world [15–18]. In Africa, for example, spina bifida has been recorded as being low in occurrence in comparison to other birth defects but questions have arisen with regard to record-taking and data management [19]. Gender preponderance differs according to country; in the USA, spina bifida is thought to be more prevalent in girls than in boys [20, 21].
4. Pathogenesis
Spina bifida aperta (SBA), sometimes referred to as spina bifida cystica, is usually visible at birth as an exposed neural tissue with or without a protruding sac at the site of the lesion. SBA may be referred to as either myeloschisis (Figure 1(a)) or myelomeningocele (Figure 1(b)). Myelomeningocele is when the spinal cord protrudes from the spinal canal into a fluid-filled sac resulting from incomplete closure of the primary neural tube. Myeloschisis is when the incomplete closure of the primary neural plate results in a cleft spinal cord with the edges flush with the defect. The extent and severity of the neurological deficits depend on the location of the lesion along the neuraxis [22].
Schematic representation of the open (aperta) and close (occulta) types of spina bifida. (a) Myeloschisis which represents the most severe form of open spina bifida. (b) Myelomeningocele which represents another typical severe form of open spina bifida (spina bifida aperta/spina bifida cystica). The typical representation is that of the spinal cord lying outside the spinal canal. (c) Meningocele that represents open or close spina bifida (the skin may or may not be present) but spinal cord does not lie outside the spinal canal. (d) Lipomyelomeningocele that represents closed spina bifida (spina bifida occulta) (covered with skin) but spinal cord is intermeshed with lipid globules (in yellow). (e) Lipomeningocele that exhibits closed spina bifida but spinal cord does not lie outside spinal canal even though lipid globules are present. (f) Spinal dorsal dermal sinus tract; spina bifida occulta with vertebral arches missing (often asymptomatic and is thought to be a mesodermal defect and a defect of secondary neurulation).
Meningocele (Figure 1(c)) is often described as a less severe variant of myelomeningocele in which the spinal cord is not found in the sac and is described by embryologists to be absent of neural matter in its herniated sac; and its description is often coupled with that of myelomeningocele which clearly has neural matter herniating at the site of the open lesion. Therefore, the status of meningocele being an open (aperta) or closed (occulta) defect is still debatable in terms of embryogenesis. However, imaging evidence by radiologists has firmly placed meningocele as spina bifida occulta [3, 7, 121–123].
Myelomeningocele (MMC) is usually associated with a type II Chiari hindbrain malformation, ventriculomegaly, and hydrocephalus [124, 125]. Chiari type II malformation is the downward displacement of the cerebellar vermis into the cervical vertebral canal [22, 125]. It is often symptomatic and is diagnosed prenatally with ultrafast fetal magnetic resonance imaging (MRI) [126, 127]. This malformation causes elongation of the brain stem and obliteration of the fourth ventricle, leading to obstruction of cerebrospinal fluid circulation and development of hydrocephalus in 90% of patients [22]. Treatment of such accompanying hydrocephalus is needed in about 82% of cases and involves draining of cerebrospinal fluid into either the peritoneal or other body cavity via a subcutaneous shunt [128].
Spina bifida occulta (SBO) is the second major form of NTDs, where the site of the lesion is not left exposed [129, 130]. Spina bifida occulta encompasses lipomyelomeningocele (Figure 1(d)), lipomeningocele (Figure 1(e)), and spinal dorsal dermal sinus tract (Figure 1(f)) ranging phenotypically from (i) dysplastic skin, (ii) tuft of hair, and (iii) vestigial tail as well as other forms of spinal dysraphism, which lack a pathogenic representation when the vertebrae develop abnormally leading to absence of the neural arches [131, 132]. In symptomatic cases, tethering of the spinal cord within the vertebral canal can result in pain, weakness, and incontinence in otherwise normal, healthy children or adults [133].
5. Treatment and Management
Management of patients with myelomeningocele has improved drastically from the mid-1970s when patients were sometimes denied treatment based on the severity of their condition [134] to the current state-of-the-art prenatal in utero repairs performed at highly specialized centers [127, 128]. Neonatal surgical closure of the lesion is considered the standard of care against which all novel management options are compared [22, 135, 136].
NTDs have a profound impact on society. The morbidity and mortality rates of spina bifida patients decrease with improving medical care. Taking the United Kingdom as an example, Bowman et al. [137] in their 25-year follow-up of 71 spina bifida aperta patients found that at least 75% of these children can be expected to reach their early adult years [137]. Moreover, as many as 85% are attending or have graduated from high school and/or college. More than 80% of young adults with spina bifida have social bladder continence. In the same study, 49% had scoliosis, with 43% eventually requiring a spinal fusion. Approximately one-third of patients were allergic to latex, with six patients having experienced a life-threatening reaction. Renal failure was 6.8–9.0 times more common for males and 9.2–11.5 times more common for female patients compared with the general population in each of the years 1994–1997 in the UK [138]. Therefore, longer life equates with the need for progressively better quality of life.
The sequelae of NTDs are staggering and appear to have not only anatomical effects secondary to the primary defect but also functional, emotional, and psychological morbidities including bladder and bowel incontinence, paralysis, musculoskeletal deformity, and shunt malfunctions and infections, among others. Moreover, the costs involved in maintenance of spina bifida patients include mobility aids (orthoses, wheelchairs, and crutches), medications, and the cost associated with shunt revisions, in addition to the cost of modifications to public utilities that are required to enable disabled access. Ultimately, its compound nature results in an immense financial burden amounting to $1,400,000 per child affected by NTD over a 20-year life span [139–142].
5.1. Syndromic and Nonsyndromic (Isolated) Spina Bifida
A small proportion of NTDs in live born infants are associated with specific syndromes that are associated with chromosomal or single-gene disorders [143]. NTDs are currently considered as “complex” disorders with genetic and environmental factors playing roles in causation [144], which have been summarized in Table 1. Craniorachischisis and encephalocoele have the highest rate of syndromic association, anencephaly and high spina bifida have intermediate rates, and caudal spina bifida has the lowest rate [145]. The role of folic acid in preventing syndromic NTDs turned out to be not as gratifying as for nonsyndromic (isolated), multifactorial NTDs [146]. It should be noted that while syndromic NTDs may have identifiable genetic causes, many of the nonsyndromic (isolated) NTDs have unidentified genetic etiology. Most of human neural tube defects are nonsyndromic with NTD being the only defect. The focus of this review paper is on nonsyndromic (isolated) spina bifida apart from the clearly stated syndromic spina bifida mentioned specifically in Table 1.
Comprehensive list of syndromic spina bifida.
Mode of inheritance
Condition
References
Autosomal recessive
(1) Jarcho-Levin syndrome (spondylocostal dysostosis): shortened trunk, opisthotonus position of the head, short neck, barrel-shaped thorax, multiple wedge shaped and block vertebrae, spina bifida, and rib anomalies.(2) Cerebrocostomandibular syndrome: Pierre Robin anomaly, speech difficulties, severe micrognathia with glossoptosis, small thorax with rib-gap defects, occasional intellectual impairment, and spina bifida.(3) Human athymic nude/SCID: T-cell defect, congenital alopecia, nail dystrophy, and spina bifida. (4) Neu-Laxova syndrome: spina bifida, severe intrauterine growth retardation, microcephaly, protruding eyes, abnormal skin, and limb defects.(5) PHAVER syndrome: spina bifida, pterygia, heart defects, segmentation defects of the spine, and radioulnar synostosis.
[23–35]
Autosomal dominant
(1) DiGeorge syndrome: hypocalcemia, parathyroid hypoplasia, thymic hypoplasia, conotruncal cardiac defects, and facial features. A case of associated spina bifida was reported.(2) Waardenburg syndrome: Type I, wide bridge of the nose, lateral displacement of the inner canthus, pigmentary disturbance of frontal white blaze of hair, heterochromia iridis, white eye lashes, leukoderma, cochlear deafness, and spina bifida. Type III, partial albinism, blue eyes, deaf-mutism, undeveloped muscles, fused joints in the arms, skeletal dysplasia, and spina bifida.(3) Sacral defect with anterior meningocele (SDAM): sacral agenesis and spina bifida.(4) Czeizel-Losonci syndrome: split hand/split foot, hydronephrosis, and spina bifida.
[36–45]
X-Linked
(1) Focal dermal hypoplasia (male lethality, atrophy and linear pigmentation of the skin, papillomas of skin and mucosae, ocular defects, hypoplastic teeth, and digital anomalies apart from spina bifida).(2) Zic3 (spina bifida with abdominal situs inversus, complex cardiac defects, asplenia, and polysplenia).(3) Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome).
[46–48]
Sporadic
(1) Isolated hemihyperplasia: asymmetric overgrowth of one or more regions with one reported case of lumbar myelomeningocele.(2) Diprosopus: conjoined twins consisting of one neck, one body, and a single hand with various forms of duplication of the craniofacial structures. May be associated with spina bifida.(3) Pentalogy of Cantrell: midline supraumbilical abdominal wall defect, defect of the lower sternum, defect of the diaphragmatic pericardium, deficiency of the anterior diaphragm, and congenital cardiac anomalies. Spina bifida has been reported.(4) Weissenbacher-Zweymüller syndrome: congenital neonatal rhizomelic dwarfism, metaphyseal widening of the long bones, vertebral coronal clefts, micrognathia, cleft palate, depressed nasal root, hypertelorism, protruding eyes, occasional sensorineural deafness, and spina bifida.
[49–53]
5.2. Causative Factors, Detection, and Prevention of Spina Bifida
The etiology of spina bifida is heterogeneous [147–150]. Most nonsyndromic spina bifida is thought to be of multifactorial origin [151] with influence of both genetic and environmental factors [144, 152]. Among the environmental factors associated with increased risk of spina bifida are increased pregnancy weight [153–158], maternal smoking [159–161], drug intake specifically of antiepileptic drugs [162–164], and maternal illnesses such as diabetes [165, 166] and hyperthermia [167]. Dietary factors including water chlorination [168–170], inositol intake [171], simple sugar intake [172], and the intake of trace elements and other micronutrients [173–176] have been proposed to act as either contributory or preventive factors for spina bifida. Isolated spina bifida is caused by cytogenetic abnormalities in 2–16% of cases [177–179].
Elevated levels of maternal serum alpha-fetoprotein are usually indicative of spina bifida aperta [180, 181] but can be associated with other conditions (e.g., twin gestation and abnormalities of placentation including placental lakes and placenta previa) and ultrasound is needed to confirm the diagnosis. Screening obstetrical ultrasonography is the initial routine method for the detection of NTDs during pregnancy in many countries. However, it sometimes fails to detect closed spina bifida [182, 183]. In highly specialized fetal centers, use of ultrafast fetal MRI has enabled detailed anatomical evaluation of the defect and accurate assessment of its accompanying effects [126].
It has been over 15 years since the Medical Research Council Vitamin Trial involving 33 centers around the world conclusively showed that 72% of recurrent NTD cases could be prevented by folic acid supplements in the periconceptional period [184]. A further study [185] showed that the first occurrence of spina bifida could also be prevented by folic acid. However, not all NTDs are responsive to folic acid and inositol has been shown as a possible additional therapy, based on prevention of spina bifida in folate-resistant NTDs in mice as well as the PONTI human trial [186, 187]. Calcium formate too has been shown to have preventive effects on NTD in mice but evidence is not yet forthcoming in prevention of human NTDs [188–190]. There still remains room to study whether there are other supplements out there that can prevent spina bifida.
6. Surgical Management of Spina Bifida
Surgical management of spina bifida here is discussed as a 2-point discussion: first is surgical management prior to the advent of in utero repair of open spina bifida and second is in utero repair leading to the Management of Myelomeningocele Study (MOMS) trial [128]. Postnatal repair of open spina bifida repair is a requirement in order to prevent further mechanical damage and infection. The lesion either may be closed primarily with the aid of skin and muscle flaps or may require a synthetic patch such as AlloDerm (LifeCell Corp., Branchburg, NJ) [191], gelatin, or collagen hybrid sponges [192]. In utero MMC repair in humans was first reported in the landmark paper published in 1998 [127]. However, since then, a handful of centers have been offering in utero repair. Furthermore, its popularity has increased in Europe [193]. The principle of in utero repair is to prevent the 2-hit hypothesis much described in previous literature that the child is exposed to neurological deterioration contributed first by failure of the neural tube to form and secondly by physical and chemical perturbation inflicted on the exposed neurological tissue of the open lesion [128, 194]. In an elegant experimental study, Meuli et al. [195] concluded that surgical exposure of the normal spinal cord to the amniotic space in a 75-day sheep fetus results in a MMC-type pathology at birth with clinical, histological, and morphological attributes comparable to human MMC. Heffez et al. [196] has demonstrated that spinal cord injury caused by exposure to the intrauterine milieu can be prevented by primary closure of the fetal skin incision as late as hours after creating the defect. It also demonstrated that ongoing exposure beyond 24 hours leads to spinal cord damage and permanent neurological deficit. Moreover, animal studies have previously shown that prenatal coverage of a spina bifida-like lesion preserves neurologic function and improves hindbrain herniation [195, 197, 198].
The first human prenatal repair of MMC was reported in Tulipan et al. [199]. Cumulative data suggested not only a dramatic improvement in hindbrain herniation but also increased maternal and neonatal risks including preterm labor, uterine dehiscence, and increased risk of fetal and neonatal death among others. Adzick et al. [128] investigated the effects of prenatal repair of MMC via a randomized prospective study. It reported that prenatal surgery for MMC performed before 26 weeks of gestation decreased the risk of death or need for shunting by the age of 12 months and also improved scores on a composite measure of mental and motor function, with adjustment for lesion level, at 30 months of age. Prenatal surgery also improves the degree of hindbrain herniation associated with Chiari II malformation, motor function, and the likelihood of being able to walk independently, as compared with postnatal surgery [128]. Open prenatal repair comes with an increased maternal and neonatal risk including preterm labor, uterine dehiscence, premature rupture of membranes, and increased risk of fetal and neonatal death. The main goal for prenatal repair of MMC is to achieve skin closure to prevent further damage of the placode and arrest the CSF leak.
7. Human Spina Bifida Genes
Despite the 250 mouse mutants with NTDs to date, there has yet to be a significant breakthrough for human NTD gene(s) both causal and/or associated with NTDs that can be used for genetic screening worldwide [4, 7]. The importance of finding candidate gene(s) as a genetic screening tool for potential parents cannot be undervalued as it has been estimated that the total lifetime costs for patients with spina bifida (spinal NTDs) amount to about $1.4 million in the US and more than €500k in Europe, with 37.1% of the total cost attributed to direct medical costs and the remainder in indirect costs, including the needs of the caregiver [200].
Despite observation of multiplex nonsyndromic NTD cases in multigenerational NTD families as seen in 17 US and 14 Dutch families with more than 1 NTD-affected person, there are other NTD cases that are simplex and sporadic as seen in identical twins with lumbosacral lipomyelomeningocele with no known familiar history of NTDs [201, 202]. This suggests that NTDs have a multifactorial genetic etiology.
To date, the strongest candidate thus far for a potential NTD screening gene is the methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) polymorphism in populations of non-Latin origin (meta-analysis study) [203]. In recent meta-analysis study, Zhang et al. support the significant association between C677T and NTDs in case-control studies (22 studies, 2,602 cases, and 4,070 controls) [204]. The second most studied MTHFR variant is A1298C, which did not report any significant increase in risk of NTDs [204]. Another meta-analysis study by Blom et al. (2006) reported increased risk in mothers and associated with NTD infants who are homozygous for C677T variant [205]. In spina bifida case studies, MTHFR C677T variant was clearly reported as associated gene or risk factors in Irish (451 spina bifida patients), mixed USA, mixed UK, and Italian cohort but not in other 180 Dutch patients (Table 3), while A1298C variant was reported with no association to spina bifida cases in Italian, Mexican (Yucatan), and Dutch population (Table 3). MTHFR is the most studied human spina bifida gene, as its role in folate one-carbon metabolism fits into a clear mechanism of NTD. However, the studies have not been well replicated in many other populations across the world, indicating that it is not likely to be either a major contributor or a common factor in NTD globally.
Other genes such as the planar cell polarity (PCP) genes, which have been studied in spina bifida cohorts among Italians, Americans, and the French, are VANGL1 and CESLR1 [44, 82–84]. The noncore PCP gene SCRIB has also been implicated as a spina bifida gene among the American cohort [85]. However, noncore PCP gene association needs to be explored further in larger NTD cohorts. To date, over 100 human spina bifida genes have been used to screen for spina bifida with 48 genes reported as a potential risk factor as listed in Table 3 which was reviewed in Greene et al. [93]; further candidates since then are NKX2-8, PTCH1, Glypican-5, PARD3, Paraoxonase 1, COMT, AMT, and GLDC genes [16, 17, 206–211]. All of these do not represent a potential global spina bifida gene. Therefore, a strong candidate spina bifida gene(s) for the world population has yet to be discovered.
8. Spina Bifida in Mouse
There exist more than 250 mouse models with neural tube defects, of which 74 are of spina bifida (Table 2) [4], yet there does not exist a single mouse gene which can be used to screen the orthologous human gene of neural tube defect nor spina bifida to date [212]. That said, it does not mean that the studies on the structural changes afforded by the mouse model cannot be used as a tool to understand human spina bifida. We discuss the various studies on mouse neurulation below and why it is still an invaluable tool for understanding human neurulation.
List of mouse models that exhibits spina bifida (reviewed in [4, 54]).
Irish (283 cases), mixed USA (61 cases, multiaffected families)
Mixed USA (259 cases), mixed UK (229 patients), Dutch (180 patients; 109 patients)
[55, 56, 71–73]
MTHFD1
Irish (509 mixed cases), mixed USA (259 mixed cases), Italian (142 cases), Irish (176 mixed cases)
Mixed UK (229 patients), Dutch (103 cases), Dutch (180 patients)
[55, 56, 59, 62, 71, 74–76]
MTHFR
Irish (451 cases), mixed USA (259 cases), mixed UK (229 patients), Italian (15 cases)
Dutch (180 patients), Mexican (Yucatan) (97 cases), Italian (15 cases)
[55, 56, 59, 60, 77, 78]
TYMS
Non-Hispanic white USA (264 cases), mixed USA (259 cases)
Dutch (180 patients)
[55, 56, 79]
Glucose metabolism (4 genes)
GLUT1
Mixed USA (507 cases)
[80]
HK1
Mixed USA (507 cases)
[80]
LEP
Mixed USA (507 cases)
[80]
LEPR
Mixed USA (507 cases)
[80]
DNA repair and DNA methylation (3 genes)
APE1
Mixed USA (380 patients)
[81]
XPD
Mixed USA (380 patients)
[81]
SOX18
Belgium (83 patients)
(Rochtus et al., 2016)
Folate transport (2 genes)
CUBN
Dutch (179 patients)
[55]
SLCA19A1, RFC-1
Dutch (180 patients)
Mixed USA (259 cases), mixed UK (229 patients)
[55, 56, 59]
PCP genes (4 gene)
VANGL1
Italian and mixed USA (658 patients), Italian and French (102 patients)
Mixed UK and USA (24 patients)
[44, 82, 83]
CELSR1
California (192 patients)
[84]
SCRIB
California (192 patients)
[85]
DVL1
Han Chinese cohort (20 cases)
[86]
Retinol metabolism (1 gene)
ALDH1A2
Mixed USA (318 families)
[87]
Axial development in mouse (1 gene)
T (brachyury)
Mixed USA (316 cases)
[88]
Methylation reactions (1 gene)
PCMT1
Mixed USA (152 cases)
Dutch (180 patients)
[55, 89]
Oxidative stress (2 genes)
SOD1
Mixed USA (610 trios or duos)
[90]
SOD2
Mixed USA (610 trios or duos)
[90]
Intermediate filament protein (1 gene)
LMNB1
Mixed UK, USA, and Swedish (233 patients)
[91]
Cell adhesion molecules (1 gene)
NCAM1
USA (204 patients)
[92]
A total of 40 genes reported showing association/risk factor for spina bifida as reviewed in Greene et al. [93].
8.1. Mechanisms of Neural Tube Closure
In vertebrates, the development of the CNS starts with the formation of the neural plate on the dorsal surface of the embryo during late gastrulation [213, 214]. A complex morphogenetic process transforms the neural plate into the hollow neural tube in a process known as “neurulation” [213]. Primary neurulation is responsible for formation of the neural tube throughout the brain and the spinal cord rostral to the mid-sacral level [215]. At more caudal levels, an alternative mechanism (secondary neurulation) operates whereby the neural tube is formed by canalization of a condensed rod of mesenchymal cells in the tail bud [216].
The process of neurulation in mammals and some other vertebrates is considered discontinuous because it occurs simultaneously at multiple sites along the neuraxis [215–219]. There are three points of de novo neural tube fusion in the mouse, which is the most studied mammalian model ([220]; see Figure 2(a)). Closure 1 occurs adjacent to somite 3 in embryos with 6-7 somites and progresses rostrally and caudally, closure 2 occurs at the midbrain-forebrain boundary at around the 10-somite stage and progresses caudally, and closure 3 occurs at the rostral end of the forebrain, soon after closure 2.
Points of closure in the mouse embryo and phenotypes of failure of closure of the various points along the neuraxis. (a) Schematic figure illustrating the multiple points of closure of the neural tube, directions of closure, and the different locations of neuropores in the developing embryo. (1), site of closure (1) which occurs at the level of somite 3 in the 6-7-somite embryo. Closure (1) is the initiation event of neurulation. Closure then progresses caudally and is completed by closure of the posterior neuropore (PNP) at the 29-30-somite stage of development; (2), second closure site at around the 10-somite stage; (3), closure (3) site which begins soon after closure (2). Arrows depict spreading of neural tube closure to neighbouring regions with completion of anterior neuropore closure soon after initiation of closure (3) and closure of the hindbrain neuropore at the 18–20-somite stage. (b) Phenotype resulting from failure of closure (1): craniorachischisis; (c) phenotype resulting from failure of closure (2): exencephaly; (d) phenotype of failure of the caudal wave of spinal closure, leading to an enlarged PNP and later development of spina bifida. (A), posterior neuropore; (B), branchial arches; (C), developing heart; (D), hindbrain; (E), midbrain; (F), forebrain; ANP: anterior neuropore; HNP: hindbrain neuropore.
Considering this discontinuous process of neurulation, it can be understood why NTDs are such a complex group of heterogeneous birth defects, with various phenotypic presentations. Failure of closure 1 leads to craniorachischisis (Figure 2(b)); failure of closures 2 and/or 3 causes exencephaly and/or anencephaly, respectively (Figure 2(c)), while failure of neurulation to progress from the site of closure 1 caudally along the spinal axis leads to spina bifida aperta (Figure 2(d)).
During neurulation, the neuroepithelium must undergo various structural changes in order to achieve closure. The advent of molecular biology has allowed scientists to identify the genes that are required for these structural changes to occur. The next section gives a brief overview of the research to date on how gene expression affects structural changes in neural tube development, with an emphasis on gene regulation in the spinal region.
8.2. The Structural Changes of the Mouse Neural Tube during the Process of Closure
Morphologically, the mouse neural tube undergoes distinct structural changes prior to its closure [7, 215, 221–224]. A summary of the spatiotemporal expression of genes in the mouse neural tube during neurulation is as shown in Table 5. The neuroepithelium narrows and lengthens, a process referred to as convergent extension (Figure 3(a)), in which the polarized cells which form the neuroepithelial plate converge towards the midline, elongate anteroposteriorly, and then intercalate [215, 225].
Schematic representation of the formation of the mouse spinal neural tube. Process of closure of the PNP of embryos undergoing Mode 1 (a, b, d) or Mode 2 (a, c, d) neurulation. (a) Neuroepithelium thickens and converges; (b) formation of bilateral neural folds which are elevated (Mode 1); (c) apposing tips of neural folds aided by bending at the dorsolateral hinge points (DLHP) of the bilateral neural folds (Mode 2); (d) adhesion and fusion at the tips of the neural folds; (e) remodeling of the neural tube. Ne, neuroepithelium; Se, surface ectoderm; Me, mesoderm; MHP, median hinge point; DLHP, dorsolateral hinge points; POAF, point of adhesion and fusion; Nt, notochord.
Convergent extension leads to narrowing and lengthening of the neuroepithelium, a process that has been suggested also to assist neural fold elevation via axial elongation [105, 226–228]. However, the lengthening of the body axis is disrupted by manipulation of gene function required for convergent extension; whilst the neural folds are still able to elevate, convergent extension still fails [227, 229, 230]. Hence, convergent extension and neural fold elevation are separable processes. Elevation of the neural folds at high levels of the spinal neuraxis results from the formation of a median hinge point (MHP) (Figure 3(b)) in a process termed Mode 1 neurulation [215, 231, 232]. The neural folds remain straight along both apical and basal surfaces, resulting in a neural tube with a slit-shaped lumen. Mode 1 neurulation occurs during formation of the spinal neural tube in 6–10-somite stage embryos, as shown in Figures 4(a) and 4(b).
Schematic figure showing progressive developmental stages of the mouse embryo and sections through the PNP at these stages. (a) Schematic of embryo at 6–10-somite stage, which has already undergone closure (1); (b) section through PNP of (a), depicting Mode 1 neurulation; (c) schematic of embryo at 12–15-somite stage; (d) section through PNP of (c) exhibiting Mode 2 neurulation; (e) schematic of embryo which has undergone closures (1), (2), and (3) with PNP being the only remaining unfused section of the neural tube; (f) section through PNP of (e) depicting Mode 3 neurulation.
A second set of hinge points are formed dorsolaterally at more caudal levels of the spinal neuraxis, the dorsolateral hinge points (DLHPs), a process that appears to enhance the ability of the apposing tips of the neural folds to come close to each other (Figure 3(c)). Mode 2 occurs during formulation of the spinal neural tube in 12–15-somite stage embryos and generates a diamond-shaped lumen, as depicted in Figures 4(c) and 4(d). In Mode 2, a median hinge point is also present, whereas the remaining portions of the neuroepithelium do not bend. At the 17–27-somite stage, the neural tube closes without a median hinge point, whereas dorsolateral hinge points are retained. This is known as Mode 3 neurulation and generates an almost circular shaped lumen, as shown in Figures 4(e) and 4(f).
Adhesion of the tips of the apposing neural folds is the final step in primary neurulation, enabling the neural tube to complete its closure [215]. The tips of the apposing neural folds and the eventual point of adhesion are reported to contain cell to cell recognition molecules (as demonstrated in red in Figure 3(c)) which may be required for the specific adhesion process to occur [233–243]. This is supported by previous evidence that the cell surface of the neuroepithelium is lined by carbohydrate-rich material that is not observed in the rest of the neuroepithelium [238]. Removal of GPI-anchored proteins from the cell surface during neurulation results in delayed spinal neural tube closure [244]. Interestingly, work performed by Abdul-Aziz et al. and Pyrgaki et al. demonstrated protrusions emanating from the neural fold tips that interdigitate leading to eventual adhesion [244, 245] (Figure 3(d)). Ultimately, the newly formed neural tube undergoes remodelling via apoptosis to enable the neural tube to separate from its surface ectoderm [228, 246] (Figure 3(e)).
8.3. Primary Neurulation Versus Secondary Neurulation
Primary neurulation and secondary neurulation are important developmental processes and have been described in many models. In the chick, there does not exist a clear distinction as to when primary neurulation ends and secondary neurulation begins; the lower spinal cord has been described as junctional neurulation, whereby ingression and accretion accompany the process of defining the area which straddles primary and secondary neurulation and is therefore thought to somehow represent human thoracolumbar spina bifida [247].
In mouse and humans, spina bifida occulta has largely been described as a result of failure of secondary neurulation [3, 215]. However, much has been described of the severity of lipomyelomeningocele [131, 248] in comparison to the somewhat neurologically unperturbed tethered cord phenomenon which is brought on by trapped nerves due to missing vertebral arches [133]. What is evident is that, irrespective of whether or not there is skin covering the neural tube defect lesion, the severity of the condition depends on the level where the site of the lesion is located. Secondary neurulation in the mouse is described as occurring at sacral level 2 [224]. Therefore, to describe lipomyelomeningocele as resulting from failure of secondary neurulation would be artificial.
9. The Genetics behind the Structural Changes in Spinal Neural Tube Closure
This section summarizes the various genes that are switched on during neurulation and whose functions have been implicated in the various structural changes that the spinal neural tube undergoes in order for closure to be achieved.
9.1. Planar Cell Polarity and Convergent Extension
Planar cell polarity (PCP) is a process in which cells develop with uniform orientation within the plane of an epithelium [249]. The PCP pathway is a noncanonical Wnt pathway [225, 250–252]. Various Wnt molecules are known to play roles in the PCP pathway such as Wnt11 and Wnt5a [250, 253].
PCP signaling has been suggested to be primarily required for cytoskeletal activity, for example, cellular protrusion, cell-cell adhesion, and cell-matrix adhesion [254]. Skin development, body hair orientation, polarization of the sensory epithelium in the inner ear, and the directed movement of mesenchymal cell populations during gastrulation are among the processes requiring proper PCP signaling in vertebrates [227, 254–256]. In vertebrates, function of the PCP pathway appears to be required for convergent extension (CE). Lamellipodia have been the type of cell shown to drive CE. These broad sheet-like protrusions exert traction on adjacent mesodermal cells causing mediolateral intercalation [257–259]. PCP signaling causes the regulation of cytoskeletal organization that redistributes subcellular PCP components asymmetrically causing polarization of these cells [260]. Moreover, components of the signaling cascade converge or are expressed asymmetrically in the lamellipodia [250, 253].
Among the genes implicated in this net movement of cells, known as convergent extension, are 2 asymmetric molecular systems that control PCP behaviour, the “core” genes and the “Fat-Dachsous” PCP system [261, 262]. The “core” genes give rise to multipass transmembrane proteins: Frizzled (Fzd-3, -6, and -7), Van Gogh (Vangl-1 and -2), Flamingo (Celsr-1, -2, and -3), and cytosolic components, Dishevelled (Dvl-1, -2, and -3), Diego (Inversin), and Prickle (Pk-1 and -2) [263]. The Fat-Dachsous (Ft-Ds) pathway includes the large protocadherins Ft and Ds, acting as its ligand, and Four-jointed (Fj) as a Golgi resident transmembrane kinase [264]. Downstream of the PCP system are PPE (Planar Polarity Effector) genes: Inturned (In), Fritz (Frtz), and Fuzzy (Fy) [265, 266]. The Multiple Wing Hairs (mwh) act downstream of both PCP and PPE [267] with Wnt4, Wnt5a, Wnt7a, and Wnt11 as regulators [263].
Vangl-2 (formerly known as Ltap and Lpp1) has been identified as the causative gene in the loop-tail mouse [105, 268, 269]. Mutations in Celsr-1 cause craniorachischisis in the Crash mouse [270]. The Dvl-1/Dvl-2, Dvl-2/Dvl-3, Dvl-2/Vangl-2, and Fzd-3/Fzd-6 double knockout mice also have severe NTD forms, mainly craniorachischisis and exencephaly [269, 271–273]. The Vangl-1 and Vangl-2 compound heterozygote exhibits craniorachischisis [274]. The noncore PCP genes also exhibit severe NTD in their mouse mutants including Protein Tyrosine Kinase 7 (PTK7), Scribbled PCP protein, the gene responsible for the circle tail mouse phenotype, Scrib, and Dishevelled Binding Antagonist of Beta-Catenin 1 (Dact-1) [252, 270, 274–277]. All of these genes have been implicated in the PCP pathway. Failure of convergent extension results in an open neuraxis (the entire neural tube from midbrain to low spine remains exposed) and a shortened embryo, more commonly described as craniorachischisis.
9.2. Neural Fold Elevation and Bending
Dorsoventral patterning in the neural development of vertebrates is controlled by the induction and polarizing properties of the floor plate [278]. Expression of various genes such as sonic hedgehog (Shh), bone morphogenetic protein (BMP) 7, HNF3β, and Vangl-1 emanating from the notochord and floor plate is thought to cause cell specification which influences the morphogenesis of the neural tube [106, 107, 112, 113, 252]. The floor plate and notochord appear to control the pattern of cell types that appear along the dorsoventral axis of the neural tube [226, 278]. Morphogenesis of the spinal neural tube, in particular, the formation of the median hinge point (MHP), is most likely a nonneuroepithelial cell autonomous action as it is dependent on the differentiation of ventral cell types by signals transmitted from axial mesodermal cells of the notochord to overlying neuroepithelial cells [278–284].
Implantation and ablation experiments which manipulated the notochord in both chick and mouse embryos [221, 284–287] verified that the notochord is required for formation of the MHP. It was proposed that the notochord releases a morphogen that may regulate MHP formation. Shh protein is expressed in the notochord at this stage [113, 288] and application of either Shh-expressing cells or purified protein to intermediate neural plate explants leads to induction of the floor plate [113], suggesting that Shh is the MHP-inducing morphogen. However, MHP formation is not totally abolished in Shh-null mouse embryos, suggesting that other factors from the notochord may also have MHP-inducing properties [287].
The second site of neural fold bending as described in Section 8.2 and Figure 3(c) is the dorsolateral hinge point (DLHP). Bending of the neuroepithelium at the DLHP is regulated by mutually antagonistic signals external to the neural fold, as reviewed by Greene and Copp [224, 289]. In contrast to midline bending, Shh has been shown to inhibit dorsolateral bending in the mouse [287] consistent with an absence of NTDs in Shh-null embryos. Signal(s) arising from the surface ectoderm (SE) comprise(s) a second antagonistic signal involved in the regulation and formation of the DLHPs [290]. This has been suggested as further evidence that bending of the neural folds involves signaling from the SE. Bone morphogenetic proteins (BMPs) are candidates to mediate this signaling. Three BMPs (BMP2, BMP4, and BMP7) are expressed in the spinal neural tube. BMP2 and BMP7 are expressed in the surface ectoderm adjacent to the open spinal neural tube, while BMP4 is expressed in the surface ectoderm overlying the closed spinal neural tube [291].
Recent studies suggest that Noggin may also play a role in regulating DLHP formation [292, 293]. Noggin is an inhibitor of BMP signaling and is expressed at the tips of the apposing neural folds [293, 294]. Homozygous mouse embryos null for Noggin exhibit both exencephaly and spina bifida (100%) [292, 295]. However, spina bifida does not arise in homozygous Noggin mutants until embryonic day 11-12 when the neural tube ruptures. The spinal neural tube of homozygous null Noggin embryos during neurulation takes on the appearance of a wavy neural tube before the neural tube reopens [293], possibly suggesting an unstable initial closure mechanism. Shh works in an antagonistic manner towards Noggin, as does Noggin towards BMP signaling [296]. This suggests that Noggin may facilitate bending of the spinal neural tube [293] by overcoming the inhibitory influence of BMPs.
Stottmann et al. [293] suggest that the spinal defect in Noggin null embryos results from a failure to maintain a closed neural tube due to a defective paraxial mesoderm [293]. Yip et al. [297] also had shown that the mesodermal extracellular matrix plays an important role in maintaining neuroepithelial rigidity of the spinal neural tube during neurulation [297]. Embryos were cultured in the presence of chlorate, which functions to inhibit sulfation of heparan sulphate proteoglycans (HSPGs) in the extracellular matrix of the mesoderm. This treatment not only resulted in an expedited bending of the DLHPs but also elicited an unnatural shape of neural tube due to a convex shaped mesoderm. However, removal of the paraxial mesoderm does not prevent closure of the spinal neural tube [287].
Interestingly, there are 3 genes which, when mutated, not only affect paraxial mesoderm production in the mouse [109, 292, 298] but also result in an NTD phenotype in the mouse. These are Cyp26, Noggin, and Fgfr1 [94, 109, 293]. The Wnt3a [299], Lef1/Tcf1 double null [108] and Raldh2 [300] mutants also have defective paraxial mesoderm production, with an abnormal neural tube during neurulation. Whether or not the paraxial mesoderm plays a primary role in successful neurulation in these mutants remains unknown.
Neural tube closure does not depend exclusively on the MHP or DLHPs, since closure can occur in the absence of either, as in Mode 3 and Mode 1 spinal neurulation, respectively. However, cell shape changes of some type, affecting morphogenesis of the spinal neural tube, are clearly required for closure to occur in all species studied, including the mouse [254]. Table 5 demonstrates the lack of specific expression of genes at the DLHPs. However, overlapping gene expression throughout the neuroepithelium and tips of neural folds may facilitate the bending mechanism seen in the DLHPs.
9.3. Adhesion of the Neural Folds
In all animal species studied, a zone of altered cell morphology with numerous rounded cell blebs has been observed along the tips of the spinal neural folds, immediately prior to adhesion. The observed surface alterations may reflect a change in the properties of the cells at the adhesion site which correlate with initial adhesion between the folds [234, 236, 301, 302]. Structural observations of the point of adhesion in human embryos have yet to be reported, possibly due to insufficient or poor preservation of material so that surface structures cannot be observed.
Adhesion is the final process in the sequence of primary neurulation events. Such physical zippering state of the neural tube has been suggested, in previous studies, as evidence that neural tube closure is a continuous process [303]. However, a debate exists as to whether the physical process of neurulation actually equates to continuous zippering or, more accurately, to a button-like process in which neural tube adhesion initially occurs at various slightly separated points along the axis. According to the latter idea, neural tube adhesion is actually a discontinuous process of closure [222].
PCP regulation may play a role in adhesion and fusion as suggested in both zebrafish and Xenopus studies. Firstly, cell division regulated by PCP signaling leads to rescue of neural tube morphogenesis in the trilobite zebrafish mutant [304]. Secondly, the Xenopus adhesion molecules, NF-protocadherin, and its cytosolic partner TAF1/Set have been suggested to participate in CE after the neural folds are formed. Disruptions in NF-protocadherin and TAF1 can lead to a shortened AP axis that was not evident until stages 22–25, some time after neural tube closure [305].
Ultrastructures that emanate from the neural folds at the site of closure have been regarded as a secondary process in the frog. This is because wound healing which acts via actin purse-string contraction is thought to be the primary cause of closure in the frog neural tube [306]. Adhesion of the neural tube and epidermis have been suggested to be separate events based upon the observation that the epidermal ectoderm is still able to migrate and cover the open neural tube in both the chick and the frog [302, 305]. However, the issue of whether or not the neural folds could adhere even in the absence of epidermal fusion in both the chick and the frog has yet to be answered.
Adhesion in the neural tube of rodents has been described previously but the mechanism of this highly specialized process is poorly understood [103, 240, 243, 301, 307, 308]. In a recent study, a direct requirement was shown for the binding of a specific ligand (ephrinA5) to a specific type of receptor (EphA7) in order to enable adhesion to occur in the neural tube [243].
Cell to cell adhesion provides impetus for positional cell migration [309]. This may suggest that PCP driven events in the surface ectoderm may play a role in neural tube closure, as suggested in the chick embryo [310]. Epidermal constriction has also been shown to be crucial for spinal neural tube closure in the frog, while the surface ectoderm was shown to be necessary for spinal neural tube closure in the mouse [287, 311].
10. Mouse Mutant Models with a Spinal Defect, Not a Neural Tube Defect
Table 4 summarizes the ten mouse mutant models that exhibit a spinal defect alone. Spinal defects encompass mouse mutants with spina bifida (without any other NTD phenotype, e.g., exencephaly and/or craniorachischisis) and abnormal spinal neural tubes with no spina bifida.
Mutant name
Gene mutated
Function of protein
Possible mechanism of NTD
Schematicrepresentations of ectopic spinal neural tube
Tips of neural folds (surface ectoderm)Grainyhead-like 3 (in neural ectoderm at E8.5) [116]Par1 and Par2 [120]
The mutants which display only spina bifida are the FGFR1α chimeric mutant [94], Traf4 mutant [95], the Shp2 chimeric mutant [96], the axial defects mutant [97], glial cell missing-1 [98], and vacuolated lens [99].
All of these mutants have spina bifida, which denotes incomplete closure of the spinal neural tube. A large majority (4 out 6 of these mutants which have only spina bifida) have a second phenotype that is a second neural tube. Vacuolated lens mutant embryos develop spina bifida and, in addition, an ectopic neural tube is observed, ventral to the open neural tube [99]. In Shp2, FGFR1α, and vacuolated lens mutants, an ectopic neural tube is observed during the period of neurulation between E8.5 and E9.5 [94, 96]. In contrast, an ectopic neural tube has only been observed at E12.5 and later stages in Gcm1 mutant embryos [98].
The prevalence of an ectopic neural tube in 2 out of 6 mutants at E9.5–E10.5 seems to suggest that a second neural tube may be a common occurrence and that this predisposition may be the result of an underlying fault in primary neurulation instead of failure of secondary neurulation.
There are many different examples of mouse mutants in which the caudal neural tube is abnormal but the phenotype differs from spina bifida. In many cases, these are described as spinal neural tube defects [100–103]. Apart from the 3 mutants with only spina bifida (Fgfr1, Shp2, and Gcm1) which have 2 neural tubes with one notochord, 2 other mutants with spinal defect but no spina bifida share the same predicament. These are the EphA2 null mouse [101] and PAK4 null mouse [100]. Another abnormal spinal neural tube phenotype is a wavy spinal neural tube that occurs in the WASP null mouse and the Vinculin null mouse [102, 103]. Vinculin is a large protein that binds multiple cytoskeletal proteins, actin, α-actinin, talin, paxillin, VASP, ponsin, vinexin, and protein kinase C (PKC) which have been suggested to be the adhesion scaffold that connects early adhesion sites to actin-driven protrusive machinery in enabling motility [312].
Abnormal and ectopic spinal neural tubes may be regarded as variant forms of NTDs as it may be possible that the neural tube reopens after closure due to various reasons. Ectopic neural tube may take on many different variations apart from the expected second or multiple neural tubes. Among them are a neural tube positioned above another neural tube as well as a wavy neural tube phenotype that is observed in many knockout mice with NTDs. The wavy region in these knockout mice has not had its spinal neural tube sectioned; thus it remains unknown whether the neural tube remains adhered. Spina bifida occulta in humans is usually accompanied by various physical abnormalities such as lipoma, rachischisis, hair tufts, ectodermal sinuses, skin pigmentation, or diastematomyelia. These associated defects occur in either syndromic or nonsyndromic NTDs. However, they may be missed and not categorized properly in cases of transgenic mice with possible NTDs. There is only one example of a null mouse in which these abnormalities have been well described which is the Gcm1 mouse mutant that exhibits both open (meningomyelocele) and close (lipoma and diastematomyelia) spina bifida in its litters [98].
11. Haploinsufficiency in Mouse and Man
Haploinsufficiency is poorly studied in both man and mouse. Furthermore, the study of the occurrence of spina bifida in genes acting in an additive or subtractive manner is almost unknown. Currently, there are 5 studies in the mouse, which have demonstrated spina bifida and the interaction of the involved genes mechanistically. These include Lrp6 and Wnt5a [313], Zac1 and Suz12 [314], Hira and Pax3 [315], Rybp encompassing Ring1 and YYP1 [316], and haploinsufficiency of the components in the primary cilium of the hedgehog pathway [317].
The scenario in humans is somewhat similar in that there are 4 studies to date demonstrating the involvement of haploinsufficiency in the causation of spina bifida. The Pax3 gene and the EphA4 gene act in concert with each other in causing spina bifida due to interstitial deletion at position 2q36 [318]. Furthermore, in the same paper, Goumy et al. [318] suggested that a similar phenomenon occurs in the mouse when taking into account the spina bifida phenotype seen on the Splotch mouse that is affected by both Pax3 [93] and EphA4 [319], albeit the link between the two in the mouse has yet to be ascertained. The hedgehog pathway has also been implicated in humans, where spina bifida occurs when Patched is perturbed when implicated with Gorlin syndrome [320]. The third and fourth studies implicating human spina bifida involve haploinsufficiency in the region of 13q [321] and 7q [322].
12. Conclusion
This review paper aims to probe spina bifida, the surviving form of neural tube defects, closely and to analyze the relationship of what can be learnt from the mouse model of spina bifida and to use that knowledge in order to shine a brighter understanding with regard to the human form.
What is very obvious is that there have been a multitude of genes (74 according to this review) which regulate specifically spina bifida in the mouse. This is a very high number of genes; therefore the take home message would be in our opinion that there are a multitude of genes that can, if perturbed, cause spina bifida. Whether or not these genes cause the condition or are in fact a player in a pool of numerous genes, which can do the job of closing the spinal neural tube, is a tantalising idea. Therefore, we put forth the idea that perhaps these 74 may be working with other genes in their family or other genes which share a common pathway in order to close the neural tube. Furthermore, the idea of gene-gene interaction which promotes heterogeneity among genes is incomplete without also considering the idea of haploinsufficiency of genes, where many mutations in mankind are somehow protected from having a deleterious phenotype by having other genes compensate the job of the gene or genes being perturbed. A very good example of this would be the Vangl-1 and Vangl-2 compound heterozygote mouse mutant which lacks a single allele of both Vangl-1 and Vangl-2; therefore the probability that the 2 genes compensate each other is high and both genes are required in a certain amount of dose, lack of which translates into a neural tube defect phenotype. Therefore, the mouse model which examines the delineation of genes has not completed its true worth until scientists understand the biology of the disease or condition better by also taking into account (i) the amount (the functioning allele) of the said gene and (ii) the interaction with other genes in its family which may be able to compensate its function as well as (iii) the interaction with other genes which share a common pathway. The mouse is a powerful tool to study spina bifida because it is a mammal like humans and its embryology is similar to humans and therefore it is an indispensable tool to mechanistically study the structural changes involved in spinal neural tube closure. The genes involved in spinal neural tube defects may differ in man and mouse; however, parallels may be drawn between the principles of how the genes interact in influencing spinal neural tube closure in both man and mouse.
Competing Interests
The authors declare that they have no competing interests.
Acknowledgments
This paper is supported by High Impact Research Grant from the University of Malaya to Noraishah M. Abdul-Aziz (UM.C/625/1/HIR/062–J-20011-73595 and UM.C/625/1/HIR/148/2–J-20011-73843), High Impact Research Grant from the Ministry of Higher Education Malaysia to Noraishah M. Abdul-Aziz (UM.C/625/1/HIR/MOHE/MED/08/04–E-000032), and postgraduate grant from University of Malaya to Siti W. Mohd-Zin and Noraishah M. Abdul-Aziz (PPP PG153-2015A). The authors would like to acknowledge Professor Andrew J. Copp and Professor Nicholas D. E. Greene (University College London) for helpful discussions.
SzymanskiK. M.MisseriR.WhittamB.YangD. Y.RaposoS. M.KingS. J.KaeferM.RinkR. C.CainM. P.Quality of life assessment in spina bifida for children (QUALAS-C): development and validation of a novel health-related quality of life instrument20168717818410.1016/j.urology.2015.09.027FischerN.ChurchP.LyonsJ.McphersonA. C.A qualitative exploration of the experiences of children with spina bifida and their parents around incontinence and social participation201541695496210.1111/cch.12257CoppA. J.AdzickN. S.ChittyL. S.FletcherJ. M.HolmbeckG. N.ShawG. M.Spina bifida20151, article 1500710.1038/nrdp.2015.7HarrisM. J.JuriloffD. M.An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure201088865366910.1002/bdra.206762-s2.0-77955649698JuriloffD. M.HarrisM. J.A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects2012941082484010.1002/bdra.230792-s2.0-84867688062GreeneN. D. E.GerrelliD.Van StraatenH. W. M.CoppA. J.Abnormalities of floor plate, notochord and somite differentiation in the loop-tail (LP) mouse: a model of severe neural tube defects1998731597210.1016/s0925-4773(98)00029-x2-s2.0-0031979611CoppA. J.GreeneN. D. E.Neural tube defects—disorders of neurulation and related embryonic processes20132221322710.1002/wdev.712-s2.0-84879788031Abu-AbedS.DolléP.MetzgerD.BeckettB.ChambonP.PetkovichM.The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures200115222624010.1101/gad.8550012-s2.0-0035862977BulgakovO. V.EggenschwilerJ. T.HongD.-H.AndersonK. V.LiT.FKBP8 is a negative regulator of mouse sonic hedgehog signaling in neural tissues20041319214921591510537410.1242/dev.011222-s2.0-254255572215105374ChiangC.LitingtungY.LeeE.YoungK. E.CordenJ. L.WestphalH.BeachyP. A.Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function19963836599407413883777010.1038/383407a02-s2.0-00297774088837770DingQ.MotoyamaJ.GascaS.MoR.SasakiH.RossantJ.HuiC.-C.Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice1998125142533254396360692-s2.0-00318558599636069LawrensonR.WyndaeleJ.-J.VlachonikolisI.FarmerC.GlickmanS.A UK general practice database study of prevalence and mortality of people with neural tube defects20001466276301112873810.1191/0269215500cr371oa2-s2.0-003366380711128738ParkerS. E.MaiC. T.CanfieldM. A.RickardR.WangY.MeyerR. E.AndersonP.MasonC. A.CollinsJ. S.KirbyR. S.CorreaA.Updated national birth prevalence estimates for selected birth defects in the United States, 2004–2006201088121008101610.1002/bdra.207352-s2.0-78650206677BooN.-Y.CheahI. G. S.ThongM.-K.Neural tube defects in malaysia: data from the malaysian national neonatal registry2013595338342fmt02610.1093/tropej/fmt0262-s2.0-84885092641JinL.ZhangL.LiZ.LiuJ.-M.YeR.RenA.Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population201335125312316498410.1016/j.reprotox.2012.10.0152-s2.0-8487102147923164984WangZ.ShangguanS.LuX.ChangS.LiR.WuL.BaoY.NiuB.WangL.ZhangT.Association of SMO polymorphisms and neural tube defects in the Chinese population from Shanxi Province20136109609662-s2.0-84887660568WangZ.WangL.ShangguanS.LuX.ChangS.WangJ.ZouJ.WuL.ZhangT.LuoY.Association between PTCH1 polymorphisms and risk of neural tube defects in a Chinese population20139764094152376104910.1002/bdra.231522-s2.0-8487978498523761049WuM.ChenD. F.SasaokaT.TonegawaS.Neural tube defects and abnormal brain development in F52-deficient mice199693521102115870089310.1073/pnas.93.5.21102-s2.0-90442549258700893EkenzeS. O.AjuzieoguO. V.NwomehB. C.Neonatal surgery in Africa: a systematic review and meta-analysis of challenges of management and outcome2015385supplement 2S3510.1016/S0140-6736(15)60830-3MitchellL. E.Scott AdzickN.MelchionneJ.PasquarielloP. S.SuttonL. N.WhiteheadA. S.Spina bifida20043649448188518951555566910.1016/S0140-6736(04)17445-X2-s2.0-884426539115555669MassonR.RégnierC. H.ChenardM.-P.Corinne WendlingMatteiM.-G.TomasettoC.Marie-Christine RioTumor necrosis factor receptor associated factor 4 (TRAF4) expression pattern during mouse development1998711-2187191950712010.1016/S0925-4773(97)00192-52-s2.0-00320074089507120JobeA. H.Fetal surgery for myelomeningocele2002347423023110.1056/nejmp0200732-s2.0-0037173468GiacoiaG. P.SayB.Spondylocostal dysplasia and neural tube defects19912815153199983410.1136/jmg.28.1.512-s2.0-00259687591999834RodriguezM. M.MejiasA.Jr.HaunR. L.MataM. B.BruceJ. H.Spondylocostal dysostosis with perinatal death and meningomyelocele19941415359DuruS.CeylanS.GüvençB. H.CeylanS.Segmental costovertebral malformations: association with neural tube defects. Report of 3 cases and review of the literature199930527227710.1159/0000288102-s2.0-0032768973KauffmannE.RomanH.BarauG.DumasH.LaffitteA.FourmaintrauxA.BintnerM.RandrianaivoH.Case report: a prenatal case of Jarcho-Levin syndrome diagnosed during the first trimester of pregnancy200323216316510.1002/pd.5492-s2.0-0037329727NadkarniT. D.RekateH. L.Treatment of refractory intracranial hypertension in a spina bifida patient by a concurrent ventricular and cisterna magna-to-peritoneal shunt20052175795821563060310.1007/s00381-004-1057-52-s2.0-2314444890315630603YiS.YoonD. H.ShinH. C.KimK. N.LeeS. W.A thoracic myelomeningocele in a patient with spondylocostal dysostosis. Case report20061041374010.3171/ped.2006.104.1.372-s2.0-33644911179DaneB.DaneC.AksoyF.CetinA.YaylaM.Jarcho-Levin syndrome presenting as neural tube defect: report of four cases and pitfalls of diagnosis200722641641910.1159/0001063452-s2.0-35549001053TolmieJ. L.WhittleM. J.McNayM. B.GibsonA. A.ConnorJ. M.Second trimester prenatal diagnosis of the Jarcho-Levin syndrome198772129134355421110.1002/pd.19700702092-s2.0-00230998553554211RomeroR.GhidiniA.EswaraM. S.SeashoreM. R.HobbinsJ. C.Prenatal findings in a case of spondylocostal dysplasia type I (Jarcho-Levin syndrome)198871698899132872532-s2.0-00239279423287253HennekamR. C. M.BeemerF. A.HuijbersW. A. R.HustinxP. A.van SprangF. J.The cerebro-costo-mandibular syndrome: third report of familial occurrence19852821181212-s2.0-0022260795AmorosiA.D'armientoM.CalcagnoG.RussoI.AdrianiM.ChristianoA. M.WeinerL.BrissetteJ. L.PignataC.FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus20087343803841833901010.1111/j.1399-0004.2008.00977.x2-s2.0-4074912575918339010ManjunathN.Vijaya SreenivasC. S.New manifestations of Neu-Laxova syndrome19903515559240567010.1002/ajmg.13203501102-s2.0-00250919212405670RodeM. E.MennutiM. T.GiardineR. M.ZackaiE. H.DriscollD. A.Early ultrasound diagnosis of Neu-Laxova syndrome20012175755801149429510.1002/pd.1012-s2.0-003486407211494295SellerM. J.MohammedS.RussellJ.OgilvieC.Microdeletion 22q11.2, Kousseff syndrome and spina bifida200211211311510.1097/00019605-200204000-000072-s2.0-0036009946ChatkuptS.ChatkuptS.JohnsonW. G.Waardenburg syndrome and myelomeningocele in a family19933018384842361610.1136/jmg.30.1.832-s2.0-00274070628423616NyeJ. S.BalkinN.LucasH.KnepperP. A.McLoneD. G.CharrowJ.Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: possible digenic inheritance of a neural tube defect199875440140810.1002/(sici)1096-8628(19980203)75:4<401::aid-ajmg10>3.0.co;2-s2-s2.0-0032477782HolF. A.HamelB. C. J.GeurdsM. P. A.MullaartR. A.BarrF. G.MacinaR. A.MarimanE. C. M.A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome19953215256789762810.1136/jmg.32.1.522-s2.0-00289548407897628ShimS. H.WyandtH. E.McDonald-McGinnD. M.ZackaiE. Z.MilunskyA.Molecular cytogenetic characterization of multiple intrachromosomal rearrangements of chromosome 2q in a patient with Waardenburg's syndrome and other congenital defects200466146521520050710.1111/j.0009-9163.2004.00276.x2-s2.0-324270430615200507KujatA.VeithV.-P.FaberR.FrosterU. G.Prenatal diagnosis and genetic counseling in a case of spina bifida in a family with Waardenburg syndrome type I20072221551581713917510.1159/0000971172-s2.0-3384705275417139175ChatkuptS.SkurnickJ. H.JaggiM.MitrukaK.KoenigsbergerM. R.JohnsonW. G.Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the united states in the 1990s19944416570829009410.1212/WNL.44.1.652-s2.0-00280639678290094GardnerP. A.AlbrightA. L.“Like mother, like son:” hereditary anterior sacral meningocele—case report and review of the literature200610421381422-s2.0-33644918569KibarZ.TorbanE.McDearmidJ. R.ReynoldsA.BerghoutJ.MathieuM.KirillovaI.De MarcoP.MerelloE.HayesJ. M.WallingfordJ. B.DrapeauP.CapraV.GrosP.Mutations in VANGL1 associated with neural-tube defects200735614143214371740932410.1056/NEJMoa0606512-s2.0-3404726177317409324CzeizelA.LosonciA.Split hand, obstructive urinary anomalies and spina bifida or diaphragmatic defect syndrome with autosomal dominant inheritance1987772203204330868310.1007/BF002723952-s2.0-00232029193308683AlmeidaL.Anyane-YeboaK.GrossmanM.RosenT.Myelomeningocele, Arnold-Chiari anomaly and hydrocephalus in focal dermal hypoplasia1988304917923318941410.1002/ajmg.13203004072-s2.0-00237854373189414MathiasR. S.LacroR. V.JonesK. L.X-linked laterality sequence: situs inversus, complex cardiac defects, splenic defects198728111111610.1002/ajmg.13202801162-s2.0-0023625914GebbiaM.FerreroG. B.PiliaG.BassiM. T.AylsworthA. S.Penman-SplittM.BirdL. M.BamforthJ. S.BurnJ.SchlessingerD.NelsonD. L.CaseyB.X-linked situs abnormalities result from mutations in ZIC31997173305308935479410.1038/ng1197-3052-s2.0-169443649849354794DaneC.DaneB.YaylaM.CetinA.Prenatal diagnosis of a case of pentalogy of Cantrell with spina bifida20075321461482-s2.0-34249298683NudlemanK.AndermannE.AndermannF.BertrandG.RogalaE.The HEMI 3 syndrome. Hemihypertrophy, hemihypaesthesia, hemiareflexia and scoliosis1984107253354610.1093/brain/107.2.5332-s2.0-0021183437SharonyR.PepkowitzS. H.HixonH.MachinG. A.GrahamJ. M.Jr.Diprosopus: a pregastrulation defect involving the head, neural tube, heart, and diaphragm19932912012092-s2.0-0027496619TerrafrancaR. J.ZellisA.Congenital hereditary cranium bifidum occultum frontalis with a review of anatomical variations in lower medsagittal region of frontal bones1953611606610.1148/61.1.602-s2.0-0343554439TekkökI. H.Triple neural tube defect—cranium bifidum with rostral and caudal spina bifida—live evidence of multi-site closure of the neural tube in humans200521433133510.1007/s00381-004-1027-y2-s2.0-17044379020HarrisM. J.JuriloffD. M.Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects200779318721010.1002/bdra.203332-s2.0-33947172588FrankeB.VermeulenS. H. H. M.Steegers-TheunissenR. P. M.CoenenM. J.SchijvenaarsM. M. V. A. P.SchefferH.Den HeijerM.BlomH. J.An association study of 45 folate-related genes in spina bifida: involvement of Cubilin (CUBN) and tRNA Aspartic Acid Methyltransferase 1 (TRDMT1)200985321622610.1002/bdra.205562-s2.0-62949117622ShawG. M.LuW.ZhuH.YangW.BriggsF. B. S.CarmichaelS. L.BarcellosL. F.LammerE. J.FinnellR. H.118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects200910, article 4910.1186/1471-2350-10-492-s2.0-67649209221ZhuH.CurryS.WenS.WickerN. J.ShawG. M.LammerE. J.YangW.JafarovT.FinnellR. H.Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts?2005135327427710.1002/ajmg.a.307392-s2.0-19944381554Ebot EnawJ. O.ZhuH.YangW.LuW.ShawG. M.LammerE. J.FinnellR. H.CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population20064, article no. 361718454210.1186/1741-7015-4-362-s2.0-3384670384917184542DoudneyK.GrinhamJ.WhittakerJ.LynchS. A.ThompsonD.MooreG. E.CoppA. J.GreeneN. D. E.StanierP.Evaluation of folate metabolism gene polymorphisms as risk factors for open and closed neural tube defects20091497158515891953378810.1002/ajmg.a.329372-s2.0-6764987048019533788O'LearyV. B.MillsJ. L.Parle-McDermottA.PangilinanF.MolloyA. M.CoxC.WeilerA.ConleyM.KirkeP. N.ScottJ. M.BrodyL. C.Screening for new MTHFR polymorphisms and NTD risk200513829910610.1002/ajmg.a.308462-s2.0-25644437881Van Der LindenI. J. M.Den HeijerM.AfmanL. A.GellekinkH.VermeulenS. H. H. M.KluijtmansL. A. J.BlomH. J.The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida200684121047105410.1007/s00109-006-0093-x2-s2.0-33750704194Van Der LindenI. J. M.HeilS. G.Den HeijerM.BlomH. J.The 894G>T variant in the endothelial nitric oxide synthase gene and spina bifida risk200752651652010.1007/s10038-007-0147-02-s2.0-34249741682BrownK. S.CookM.HoessK.WhiteheadA. S.MitchellL. E.Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus200470310110610.1002/bdra.200022-s2.0-1942486384KingT. M.AuK.-S.KirkpatrickT. J.DavidsonC.FletcherJ. M.TownsendI.TyermanG. H.ShimminL. C.NorthrupH.The impact of BRCA1 on spina bifida meningomyelocele lesion20077167197281764032810.1111/j.1469-1809.2007.00377.x2-s2.0-3494885895017640328ZhuH.EnawJ. O. E.MaC.ShawG. M.LammerE. J.FinnellR. H.Association between CFL1 gene polymorphisms and spina bifida risk in a California population20078, article 1210.1186/1471-2350-8-122-s2.0-33947682250LuW.ZhuH.WenS.LaurentC.ShawG. M.LammerE. J.FinnellR. H.Screening for novel PAX3 polymorphisms and risks of spina bifida2007791454910.1002/bdra.203222-s2.0-33845967860ToepoelM.Steegers-TheunissenR. P. M.OuborgN. J.FrankeB.González-Zuloeta LaddA. M.JoostenP. H. L. J.Van ZoelenE. J. J.Interaction of PDGFRA promoter haplotypes and maternal environmental exposures in the risk of spina bifida20098576296361921502110.1002/bdra.205742-s2.0-6765116353019215021AuK.-S.NorthrupH.KirkpatrickT. J.VolcikK. A.FletcherJ. M.TownsendI. T.BlantonS. H.TyermanG. H.VillarrealG.KingT. M.Promotor genotype of the platelet-derived growth factor receptor-α gene shows population stratification but not association with spina bifida meningomyelocele2005139319419810.1002/ajmg.a.310022-s2.0-28444481727WenS.LuW.ZhuH.YangW.ShawG. M.LammerE. J.IslamA.FinnellR. H.Genetic polymorphisms in the thioredoxin 2 (TXN2) gene and risk for spina bifida2009149215516010.1002/ajmg.a.325892-s2.0-59849125876KlootwijkR.GroenenP.SchijvenaarsM.HolF.HamelB.StraatmanH.Steegers-TheunissenR.MarimanE.FrankeB.Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans2004124140472-s2.0-0942276985van der LindenI. J. M.NguyenU.HeilS. G.FrankeB.VloetS.GellekinkH.HeijerM. D.BlomH. J.Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida2007911981031733656410.1016/j.ymgme.2007.01.0092-s2.0-3404724840317336564Parle-McDermottA.PangilinanF.MillsJ. L.KirkeP. N.GibneyE. R.TroendleJ.O'LearyV. B.MolloyA. M.ConleyM.ScottJ. M.BrodyL. C.The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) May decrease rather than increase risk for spina bifida in the Irish population200714311117411801748659510.1002/ajmg.a.317252-s2.0-3424990333317486595JohnsonW. G.StenroosE. S.SpychalaJ. R.ChatkuptS.MingS. X.BuyskeS.New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy?200412443393452-s2.0-0942290719CarrollN.PangilinanF.MolloyA. M.TroendleJ.MillsJ. L.KirkeP. N.BrodyL. C.ScottJ. M.Parle-McDermottA.Analysis of the MTHFD1 promoter and risk of neural tube defects200912532472561913009010.1007/s00439-008-0616-32-s2.0-6324908543619130090De MarcoP.MerelloE.CalevoM. G.MascelliS.RasoA.CamaA.CapraV.Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G > A polymorphism for neural tube defect risk20065129810310.1007/s10038-005-0329-62-s2.0-31544464705Parle-McDermottA.KirkeP. N.MillsJ. L.MolloyA. M.CoxC.O'LearyV. B.PangilinanF.ConleyM.ClearyL.BrodyL. C.ScottJ. M.Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population20061467687721655242610.1038/sj.ejhg.52016032-s2.0-3374446020316552426GrandoneE.CorraoA. M.ColaizzoD.VecchioneG.Di GirgentiC.PaladiniD.SardellaL.PellegrinoM.ZelanteL.MartinelliP.MargaglioneM.Homocysteine metabolism in families from southern Italy with neural tube defects: role of genetic and nutritional determinants20062611510.1002/pd.13592-s2.0-31944431893Gonzalez-HerreraL.Castillo-ZapataI.Garcia-EscalanteG.Pinto-EscalanteD.A1298C polymorphism of the MTHFR gene and neural tube defects in the state of Yucatan, Mexico200779862262610.1002/bdra.203812-s2.0-34548059490VolcikK. A.ShawG. M.ZhuH.LammerE. J.LaurentC.FinnellR. H.Associations between polymorphisms within the thymidylate synthase gene and spina bifida2003671192492810.1002/bdra.100292-s2.0-0344875624DavidsonC. M.NorthrupH.KingT. M.FletcherJ. M.TownsendI.TyermanG. H.KitS. A.Genes in glucose metabolism and association with spina bifida200815151581821235410.1177/19337191073095902-s2.0-3894909687718212354OlshanA. F.ShawG. M.MillikanR. C.LaurentC.FinnellR. H.Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts200513532682731588729310.1002/ajmg.a.307132-s2.0-1994438695215887293DoudneyK.MooreG. E.StanierP.Ybot-GonzalezP.PaternotteC.GreeneN. D. E.CoppA. J.StevensonR. E.Analysis of the planar cell polarity gene Vangl2 and its co-expressed paralogue Vangl1 in neural tube defect patients20051361909210.1002/ajmg.a.307662-s2.0-21644443932KibarZ.BosoiC. M.KooistraM.SalemS.FinnellR. H.De MarcoP.MerelloE.BassukA. G.CapraV.GrosP.Novel mutations in VANGL1 in neural tube defects2009307E706E7151931997910.1002/humu.210262-s2.0-6764967014319319979LeiY.ZhuH.YangW.RossM. E.ShawG. M.FinnellR. H.Identification of novel CELSR1 mutations in spina bifida201493e922072463273910.1371/journal.pone.00922072-s2.0-8489847981424632739LeiY.ZhuH.DuhonC.YangW.RossM. E.ShawG. M.FinnellR. H.Mutations in planar cell polarity gene SCRIB are associated with spina bifida201387e6926210.1371/journal.pone.00692622-s2.0-84880827508ChenS.ZhangQ.BaiB.OuyangS.BaoY.LiH.ZhangT.MARK2/Par1b insufficiency attenuates DVL gene transcription via histone deacetylation in lumbosacral spina bifida201610.1007/s12035-016-0164-0DeakK. L.DickersonM. E.LinneyE.EnterlineD. S.GeorgeT. M.MelvinE. C.GrahamF. L.SiegelD. G.HammockP.MehltretterL.BassukA. G.KesslerJ. A.GilbertJ. R.SpeerM. C.AbenJ.AylsworthA.PowellC.MackeyJ.WorleyG.BreiT.BuranC.BodurthaJ.SawinK.DiasM. S.MackP.MeeropolE.LasarskyN.McLoneD.ItoJ.OakesW. J.WalkerM.PetersonP.IskandarB.Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A22005731186887510.1002/bdra.201832-s2.0-28444435486JensenL. E.BarbauxS.HoessK.FratermanS.WhiteheadA. S.MitchellL. E.The human T locus and spina bifida risk2004115647548210.1007/s00439-004-1185-82-s2.0-9444295405ZhuH.YangW.LuW.ZhangJ.ShawG. M.LammerE. J.FinnellR. H.A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida200687166701625638910.1016/j.ymgme.2005.09.0082-s2.0-2934444798516256389KaseB. A.NorthrupH.MorrisonA. C.DavidsonC. M.GoiffonA. M.FletcherJ. M.OstermaierK. K.TyermanG. H.AuK. S.Association of copper-zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele2012941076276910.1002/bdra.230652-s2.0-84867663614RobinsonA.PartridgeD.MalhasA.De CastroS. C. P.GustavssonP.ThompsonD. N.VauxD. J.CoppA. J.StanierP.BassukA. G.GreeneN. D. E.Is LMNB1 a susceptibility gene for neural tube defects in humans?201397639840210.1002/bdra.231412-s2.0-84879786794DeakK. L.BoylesA. L.EtcheversH. C.MelvinE. C.SiegelD. G.GrahamF. L.SliferS. H.EnterlineD. S.GeorgeT. M.VekemansM.McClayD.BassukA. G.KesslerJ. A.LinneyE.GilbertJ. R.SpeerM. C.AbenJ.AylsworthA.PowellC.MackeyJ.WorleyG.BreiT.BuranC.BodurthaJ.SawinK.DiasM. S.MackP.MeeropolE.LasarskyN.McLoneD.ItoJ.OakesJ.WalkerM.IskandarB.SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects20051172-31331421588383710.1007/s00439-005-1299-72-s2.0-2694444932715883837GreeneN. D. E.StanierP.CoppA. J.Genetics of human neural tube defects2009182R113R1291980878710.1093/hmg/ddp3472-s2.0-7394916016019808787DengC.BedfordM.LiC.XuX.YangX.DunmoreJ.LederP.Fibroblast growth factor receptor-1 (FGFR-1) is essential for normal neural tube and limb development199718514254916904910.1006/dbio.1997.85532-s2.0-00311498839169049RégnierC. H.MassonR.KedingerV.TextorisJ.StollI.ChenardM.-P.DierichA.TomasettoC.RioM.-C.Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice2002998558555901194384610.1073/pnas.0521247992-s2.0-003711751811943846SaxtonT. M.PawsonT.Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp21999967379037951009711610.1073/pnas.96.7.37902-s2.0-003361660510097116EssienF. B.HavilandM. B.NaidoffA. E.Expression of a new mutation (Axd) causing axial defects in mice correlates with maternal phenotype and age1990422183194221894510.1002/tera.14204202092-s2.0-00253413132218945Nait-OumesmarB.SteccaB.FatterpekarG.NaidichT.CorbinJ.LazzariniR. A.Ectopic expression of Gcm1 induces congenital spinal cord abnormalities20021291639573964121359322-s2.0-003667224112135932WilsonD. B.WyattD. P.Pathogenesis of neural dysraphism in the mouse mutant vacuolated lens (vl)19864514355394132610.1097/00005072-198601000-000042-s2.0-00226297583941326QuJ.LiX.NovitchB. G.ZhengY.KohnM.XieJ.-M.KozinnS.BronsonR.BegA. A.MindenA.PAK4 kinase is essential for embryonic viability and for proper neuronal development20032320712271331451728310.1128/MCB.23.20.7122-7133.20032-s2.0-014181912314517283Naruse-NakajimaC.AsanoM.IwakuraY.Involvement of EphA2 in the formation of the tail notochord via interaction with ephrinA120011021-29510510.1016/s0925-4773(01)00290-82-s2.0-0035060608SnapperS. B.TakeshimaF.AntónI.LiuC.-H.ThomasS. M.NguyenD.DudleyD.FraserH.PurichD.Lopez-IlasacaM.KleinC.DavidsonL.BronsonR.MulliganR. C.SouthwickF.GehaR.GoldbergM. B.RosenF. S.HartwigJ. H.AltF. W.N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility20013108979041158427110.1038/ncb1001-8972-s2.0-003479542311584271XuW.BaribaultH.AdamsonE. D.Vinculin knockout results in heart and brain defects during embryonic development1998125232733794868052-s2.0-00319297609486805ElmsP.SiggersP.NapperD.GreenfieldA.ArkellR.Zic2 is required for neural crest formation and hindbrain patterning during mouse development200326423914061465192610.1016/j.ydbio.2003.09.0052-s2.0-034492585914651926KibarZ.VoganK. J.GroulxN.JusticeM. J.UnderhillD. A.GrosP.Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail200128325125510.1038/900812-s2.0-0034931874AngS.-L.RossantJ.HNF-3β is essential for node and notochord formation in mouse development1994784561574806990910.1016/0092-8674(94)90522-32-s2.0-00281699928069909DoudneyK.StanierP.Epithelial cell polarity genes are required for neural tube closure2005135142471580084710.1002/ajmg.c.300522-s2.0-1784437846315800847GalceranJ.FariñasI.DepewM. J.CleversH.GrosschedlR.Wnt3a−/−-like phenotype and limb deficiency in Lef1−/−Tcf1−/− mice199913670971710.1101/gad.13.6.7092-s2.0-0344820773Abu-AbedS.DolléP.MetzgerD.WoodC.MacLeanG.ChambonP.PetkovichM.Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1200313071449145910.1242/dev.003572-s2.0-0037384994ChiH.SarkisianM. R.RakicP.FlavellR. A.Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development200510210384638511573134710.1073/pnas.05000261022-s2.0-1484435448715731347ChenJ.ChangS.DuncanS. A.OkanoH. J.FishellG.AderemA.Disruption of the MacMARCKS gene prevents cranial neural tube closure and results in anencephaly1996931362756279869280510.1073/pnas.93.13.62752-s2.0-00299578318692805SollowayM. J.RobertsonE. J.Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup1999126817531768100792362-s2.0-003291546010079236MartíE.TakadaR.BumcrotD. A.SasakiH.McMahonA. P.Distribution of Sonic hedgehog peptides in the developing chick and mouse embryo199512182537254776718172-s2.0-00290798937671817WeinsteinD. C.Ruiz i AltabaA.ChenW. S.HoodlessP.PreziosoV. R.JessellT. M.DarnellJ. E.Jr.The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo1994784575588806991010.1016/0092-8674(94)90523-12-s2.0-00280255668069910DubrulleJ.PourquiéO.fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo200442769734194221474982410.1038/nature022162-s2.0-084226418814749824AudenA.CaddyJ.WilanowskiT.TingS. B.CunninghamJ. M.JaneS. M.Spatial and temporal expression of the Grainyhead-like transcription factor family during murine development2006689649701683157210.1016/j.modgep.2006.03.0112-s2.0-3374819014016831572JhoE.-H.ZhangT.DomonC.JooC.-K.FreundJ.-N.CostantiniF.Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway20022241172118310.1128/mcb.22.4.1172-1183.20022-s2.0-0036148208GouldingM. D.ChalepakisG.DeutschU.ErseliusJ. R.GrussP.Pax-3, a novel murine DNA binding protein expressed during early neurogenesis19911051135114720221852-s2.0-00258752262022185RamosC.RobertB.msh/Msx gene family in neural development200521116246321616963010.1016/j.tig.2005.09.0012-s2.0-2644460906516169630CamererE.BarkerA.DuongD. N.GanesanR.KataokaH.CornelissenI.DarraghM. R.HussainA.ZhengY.-W.SrinivasanY.BrownC.XuS.-M.RegardJ. B.LinC.-Y.CraikC. S.KirchhoferD.CoughlinS. R.Local protease signaling contributes to neural tube closure in the mouse embryo2010181253810.1016/j.devcel.2009.11.0142-s2.0-74049143122Van Der PutN. M. J.Van StraatenH. W. M.TrijbelsF. J. M.BlomH. J.Folate, homocysteine and neural tube defects: an overview200122642432702-s2.0-0034994046Tortori-DonatiP.RossiA.CamaA.Spinal dysraphism: a review of neuroradiological features with embryological correlations and proposal for a new classification200042747149110.1007/s0023400003252-s2.0-0033859396VolpeJ. J.1995Philadelphia, Pa, USASaundersStevensonK. L.Chiari type II malformation: past, present, and future2004162, article E52-s2.0-4644293659WilliamsH.A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida20085, article 710.1186/1743-8454-5-72-s2.0-43149120887ColemanB. G.AdzickN. S.CrombleholmeT. M.JohnsonM. P.HowellL.HoriiS. C.LangerJ. E.NisenbaumH. L.DeBariS.IyoobC.Fetal therapy: state of the art20022111125712882-s2.0-0036829542AdzickN. S.SuttonL. N.CrombleholmeT. M.FlakeA. W.Successful fetal surgery for spina bifida1998352914116751676985344210.1016/S0140-6736(98)00070-12-s2.0-00325564379853442AdzickN. S.ThomE. A.SpongC. Y.BrockJ. W.IIIBurrowsP. K.JohnsonM. P.HowellL. J.FarrellJ. A.DabrowiakM. E.SuttonL. N.GuptaN.TulipanN. B.D'AltonM. E.FarmerD. L.A randomized trial of prenatal versus postnatal repair of myelomeningocele20113641199310042130627710.1056/NEJMoa10143792-s2.0-7995281032721306277EubanksJ. D.CheruvuV. K.Prevalence of sacral spina bifida occulta and its relationship to age, sex, race, and the sacral table angle: an anatomic, osteologic study of three thousand one hundred specimens200934151539154310.1097/brs.0b013e3181a985602-s2.0-67651174520FidasA.MacDonaldH. L.EltonR. A.WildS. R.ChisholmG. D.ScottR.Prevalence and patterns of spina bifida occulta in 2707 normal adults1987385537542331156510.1016/S0009-9260(87)80150-22-s2.0-00232646133311565MayL.HaywardR.ChakrabortyA.FranckL.ManzottiG.WrayJ.ThompsonD.Lack of uniformity in the clinical assessment of children with lipomyelomeningocele: a review of the literature and recommendations for the future201329696197010.1007/s00381-013-2063-22-s2.0-84878586818VenkataramanaN. K.Spinal dysraphism201163S31S4010.4103/1817-1745.857072-s2.0-80054811934IskandarB. J.FulmerB. B.HadleyM. N.OakesW. J.Congenital tethered spinal cord syndrome in adults199888695896110.3171/jns.1998.88.6.09582-s2.0-0031813101LorberJ.Selective treatment of myelomeningocele: to treat or not to treat?19745333073082-s2.0-0016042343BrunerJ. P.TulipanN.Intrauterine repair of spina bifida20054849429551628684010.1097/01.grf.0000184799.17975.e92-s2.0-2954444291516286840PiattJ. H.Jr.Treatment of myelomeningocele: a review of outcomes and continuing neurosurgical considerations among adults—a review20106651552510.3171/2010.9.peds102662-s2.0-78649892646BowmanR. M.McLoneD. G.GrantJ. A.TomitaT.ItoJ. A.Spina bifida outcome: a 25-year prospective200134311412010.1159/0000560052-s2.0-0035022188LawrensonR.WyndaeleJ.-J.VlachonikolisI.FarmerC.GlickmanS.Renal failure in patients with neurogenic lower urinary tract dysfunction20012021381431135908310.1159/0000547742-s2.0-003502412411359083IreysH. T.AndersonG. F.ShafferT. J.NeffJ. M.Expenditures for care of children with chronic illnesses enrolled in the Washington State Medicaid Program, fiscal year 199319971002197204924079910.1542/peds.100.2.1972-s2.0-00307432679240799MaciasM. M.RobertsK. M.SaylorC. F.FussellJ. J.Toileting concerns, parenting stress, and behavior problems in children with special health care needs20064554154221689127410.1177/00099228062896162-s2.0-3374748933016891274VerhoefM.BarfH. A.PostM. W. M.van AsbeckF. W. A.GooskensR. H. J. M.PrevoA. J. H.Functional independence among young adults with spina bifida, in relation to hydrocephalus and level of lesion20064821141191641766610.1017/S00121622060002592-s2.0-3114445675316417666SinA. H.RashidiM.CalditoG.NandaA.Surgical treatment of myelomeningocele: year 2000 hospitalization, outcome, and cost analysis in the US200723101125112710.1007/s00381-007-0375-92-s2.0-34548630219ChenC.-P.Syndromes, disorders and maternal risk factors associated with neural tube defects (I)2008471191840057610.1016/S1028-4559(08)60048-02-s2.0-4294916562718400576HallJ.SolehdinF.Folic acid for the prevention of congenital anomalies19981576445450966739610.1007/s0043100508502-s2.0-00318355159667396SeaverL. H.StevensonR. E.WyszynskiD. F.Syndromes with neural tube defects2006Oxford, UKOxford University PressSeidahmedM. Z.AbdelbasitO. B.ShaheedM. M.AlhusseinK. A.MiqdadA. M.KhalilM. I.Al-EnazyN. M.SalihM. A.Epidemiology of neural tube defects201435supplement 1S29S35HolmesL. B.DriscollS. G.AtkinsL.Etiologic heterogeneity of neural-tube defects1976294736536910.1056/nejm1976021229407042-s2.0-0017293829KhouryM. J.EricksonJ. D.JamesL. M.Etiologic heterogeneity of neural tube defects: clues from epidemiology198211545385482-s2.0-0020063425KhouryM. J.David EricksonJ.JamesL. M.Etiologic heterogeneity of neural tube defects. II. Clues from family studies198234698098771808522-s2.0-00202826777180852MartinR. A.FinemanR. M.JordeL. B.Phenotypic heterogeneity in neural tube defects: a clue to causal heterogeneity198316451952510.1002/ajmg.13201604102-s2.0-0021015010RampersaudE.MelvinE. C.SpeerM. C.2006Oxford University PressAguiarM. J.CamposA. S.AguiarR. A.LanaA. M.MagalhaesR. L.BabetoL. T.Neural tube defects and associated factors in liveborn and stillborn infants2003792129134DietlJ.Maternal obesity and complications during pregnancy20053321001051584325610.1515/JPM.2005.0182-s2.0-1644437519515843256HallL. F.NeubertA. G.Obesity and pregnancy20056042532601579563310.1097/01.ogx.0000158509.04154.9e2-s2.0-1574438412515795633MojtabaiR.Body mass index and serum folate in childbearing age women20041911102910361564859610.1007/s10654-004-2253-z2-s2.0-1244426064415648596AndreasenK. R.AndersenM. L.SchantzA. L.Obesity and pregnancy20048311102210291548811510.1111/j.0001-6349.2004.00624.x2-s2.0-764423305615488115WallerD. K.MillsJ. L.SimpsonJ. L.CunninghamG. C.ConleyM. R.LassmanM. R.RhoadsG. G.Are obese women at higher risk for producing malformed offspring?19941702541548811671010.1016/S0002-9378(94)70224-12-s2.0-00282268558116710RasmussenS. A.ChuS. Y.KimS. Y.SchmidC. H.LauJ.Maternal obesity and risk of neural tube defects: a metaanalysis200819866116191853814410.1016/j.ajog.2008.04.0212-s2.0-4444913413618538144JensenL. E.HoessK.WhiteheadA. S.MitchellL. E.The NAT1 C1095A polymorphism, maternal multivitamin use and smoking, and the risk of spina bifida200573751251610.1002/bdra.201432-s2.0-22944446755SuarezL.RamadhaniT.FelknerM.CanfieldM. A.BrenderJ. D.RomittiP. A.SunL.Maternal smoking, passive tobacco smoke, and neural tube defects201191129332125435610.1002/bdra.207432-s2.0-7875150663121254356WangL.JinL.LiuJ.ZhangY.YuanY.YiD.RenA.Maternal genetic polymorphisms of phase II metabolic enzymes and the risk of fetal neural tube defects20141001132110.1002/bdra.231962-s2.0-84892884175OrnoyA.Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy200622221422610.1016/j.reprotox.2006.03.0142-s2.0-33745601108YerbyM. S.Management issues for women with epilepsy: neural tube defects and folic acid supplementation2003616S23S2610.1212/wnl.61.6_suppl_2.s232-s2.0-0141765764WerlerM. M.AhrensK. A.BoscoJ. L. F.MitchellA. A.AnderkaM. T.GilboaS. M.HolmesL. B.Use of antiepileptic medications in pregnancy in relation to risks of birth defects2011211184285010.1016/j.annepidem.2011.08.0022-s2.0-80053515283FineE. L.HoralM.ChangT. I.FortinG.LoekenM. R.Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy19994812245424621058043610.2337/diabetes.48.12.24542-s2.0-003351348010580436PaniL.HoralM.LoekenM. R.Polymorphic susceptibility to the molecular causes of neural tube defects during diabetic embryopathy2002519287128741219648410.2337/diabetes.51.9.28712-s2.0-003672377712196484MorettiM. E.Bar-OzB.FriedS.KorenG.Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis200516221621910.1097/01.ede.0000152903.55579.152-s2.0-14644415866HwangB.-F.MagnusP.JaakkolaJ. J. K.Risk of specific birth defects in relation to chlorination and the amount of natural organic matter in the water supply200215643743821218110810.1093/aje/kwf0382-s2.0-003710317412181108BoveF.ShimY.ZeitzP.Drinking water contaminants and adverse pregnancy outcomes: a review2002110, supplement 1617410.1289/ehp.02110s1612-s2.0-0036180109GravesC. G.MatanoskiG. M.TardiffR. G.Weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products: a critical review200134210312410.1006/rtph.2001.14942-s2.0-0034749605CavalliP.CoppA. J.Inositol and folate resistant neural tube defects2002392E510.1136/jmg.39.2.e52-s2.0-17544402720ShawG. M.QuachT.NelsonV.CarmichaelS. L.SchafferD. M.SelvinS.YangW.Neural tube defects associated with maternal periconceptional dietary intake of simple sugars and glycemic index20037859729782-s2.0-0642310644UlmanC.TaneliF.OkselF.HakerlerlerH.Zinc-deficient sprouting blight potatoes and their possible relation with neural tube defects200523169721537623110.1002/cbf.11722-s2.0-1124426962315376231MartínI.GibertM. J.PintosC.NogueraA.BesalduchA.ObradorA.Oxidative stress in mothers who have conceived fetus with neural tube defects: the role of aminothiols and selenium200423450751410.1016/j.clnu.2003.09.0102-s2.0-4243141794GroenenP. M. W.Van RooijI. A. L. M.PeerP. G. M.GooskensR. H.ZielhuisG. A.Steegers-TheunissenR. P. M.Marginal maternal vitamin B 12 status increases the risk of offspring with spina bifida2004191111171529533810.1016/j.ajog.2003.12.0322-s2.0-404306085115295338CengizB.SöylemezF.ÖztürkE.ÇavdarA. O.Serum zinc, selenium, copper, and lead levels in women with second-trimester induced abortion resulting from neural tube defects: a preliminary study200497322523510.1385/bter:97:3:2252-s2.0-12144289385HarmonJ. P.HiettA. K.PalmerC. G.GolichowskiA. M.Prenatal ultrasound detection of isolated neural tube defects: is cytogenetic evaluation warranted?199586459559910.1016/s0029-7844(95)80023-92-s2.0-0029073378HumeR. F.Jr.DruganA.ReichlerA.LampinenJ.MartinL. S.JohnsonM. P.EvansM. I.Aneuploidy among prenatally detected neural tube defects199661217117310.1002/(sici)1096-8628(19960111)61:2<171::aid-ajmg14>3.0.co;2-r2-s2.0-0030047177CoerdtW.MillerK.HolzgreveW.RauskolbR.SchwingerE.RehderH.Neural tube defects in chromosomally normal and abnormal human embryos1997106410415947632710.1046/j.1469-0705.1997.10060410.x2-s2.0-00314521339476327DasheJ. S.TwicklerD. M.Santos-RamosR.McIntireD. D.RamusR. M.Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound20061956162316281676902210.1016/j.ajog.2006.03.0972-s2.0-3375123201216769022WaldN.HackshawA.Folic acid and prevention of neural-tube defects19973509078, article no. 6652-s2.0-0031591713AlfirevicZ.DISQ 3: failure to diagnose a fetal anomaly on a routine ultrasound scan at 20 weeks200526779779810.1002/uog.26312-s2.0-29144449998GarneE.LoaneM.DolkH.De ViganC.ScaranoG.TuckerD.StollC.GenerB.PieriniA.NelenV.RöschC.GillerotY.FeijooM.TinchevaR.Queisser-LuftA.AddorM.-C.MosqueraC.GattM.BarisicI.Prenatal diagnosis of severe structural congenital malformations in Europe20052516111561932110.1002/uog.17842-s2.0-1994443113515619321MRC Vitamin Study Research GroupPrevention of neural tube defects: results of the Medical Research Council Vitamin Study1991338876013113710.1016/0140-6736(91)90133-aCzeizelA. E.DudásI.Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation1992327261832183510.1056/nejm1992122432726022-s2.0-0027080461GreeneN. D. E.CoppA. J.Inositol prevents folate-resistant neural tube defects in the mouse1997316066898674210.1038/nm0197-602-s2.0-00310335938986742GreeneN. D.LeungK. Y.GayV.BurrenK.MillsK.ChittyL. S.CoppA. J.Inositol for the prevention of neural tube defects: a pilot randomised controlled trial2016115974983BolusaniS.YoungB. A.ColeN. A.TibbettsA. S.MombJ.BryantJ. D.SolmonsonA.ApplingD. R.Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues20112867516651742116394710.1074/jbc.M110.1968402-s2.0-7995314034321163947MombJ.LewandowskiJ. P.BryantJ. D.FitchR.SurmanD. R.VokesS. A.ApplingD. R.Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice201311025495542326709410.1073/pnas.12111991102-s2.0-8487218336323267094PaiY. J.LeungK.-Y.SaveryD.HutchinT.PruntyH.HealesS.BrosnanM. E.BrosnanJ. T.CoppA. J.GreeneN. D. E.Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice20156, article no. 638810.1038/ncomms73882-s2.0-84924209564AgagR. L.GranickM. S.OmidiM.CatramboneJ.BeneveniaJ.GlatP.DucicI.DisaJ. J.Neurosurgical reconstruction with acellular cadaveric dermal matrix20045265715771516698510.1097/01.sap.0000122651.12811.3d2-s2.0-254261541615166985WatanabeM.LiH.KimA. G.WeilersteinA.RaduA.DaveyM.LoukogeorgakisS.SánchezM. D.SumitaK.MorimotoN.YamamotoM.TabataY.FlakeA. W.Complete tissue coverage achieved by scaffold-based tissue engineering in the fetal sheep model of Myelomeningocele20167613314310.1016/j.biomaterials.2015.10.051KmietowiczZ.Plymouth mother is first UK woman to have prenatal repair of open spina bifida funded by NHS2014349g687510.1136/bmj.g68752-s2.0-84911918063StiefelD.CoppA. J.MeuliM.Fetal spina bifida in a mouse model: loss of neural function in utero200710632132212-s2.0-34248593138MeuliM.Meuli-SimmenC.YinglingC. D.HutchinsG. M.HoffmanK. M.HarrisonM. R.AdzickN. S.Creation of myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep19953071028103310.1016/0022-3468(95)90335-62-s2.0-0029093376HeffezD. S.AryanpurJ.HutchinsG. M.FreemanJ. M.The paralysis associated with myelomeningocele: clinical and experimental data implicating a preventable spinal cord injury199026698799210.1227/00006123-199006000-000112-s2.0-0025339308HeffezD. S.AryanpurJ.RotelliniN. A. C.HutchinsG. M.FreemanJ. M.HoffmanH. J.McLoneD. G.Intrauterine repair of experimental surgically created dysraphism199332610051010832707410.1227/00006123-199306000-000212-s2.0-00272985518327074MeuliM.Meuli-SimmenC.HutchinsG. M.YinglingC. D.McBiles HoffmanK.HarrisonM. R.AdzickN. S.In utero surgery rescues neurological function at birth in sheep with spina bifida199514342347758506410.1038/nm0495-3422-s2.0-00289322307585064TulipanN.BrunerJ. P.Hernanz-SchulmanM.LoweL. H.WalshW. F.NickolausD.OakesW. J.Effect of intrauterine myelomeningocele repair on central nervous system structure and function19993141831881070592710.1159/0000288592-s2.0-003338041610705927YiY.LindemannM.ColligsA.SnowballC.Economic burden of neural tube defects and impact of prevention with folic acid: a literature review2011170111391140010.1007/s00431-011-1492-82-s2.0-82655166702ChatkuptS.HolF. A.ShugartY. Y.GeurdsM. P. A.StenroosE. S.KoenigsbergerM. R.HamelB. C. J.JohnsonW. G.MarimanE. C. M.Absence of linkage between familial neural tube defects and PAX3 gene1995323200204778316910.1136/jmg.32.3.2002-s2.0-00289569447783169HanaeiS.NejatF.MortazaviA.HabibiZ.EsmaeiliA.El KhashabM.Identical twins with lumbosacral lipomyelomeningocele201515192952539670110.3171/2014.10.PEDS14942-s2.0-8492502806625396701AmorimM. R.LimaM. A. C.CastillaE. E.OrioliI. M.Non-Latin European descent could be a requirement for association of NTDs and MTHFR variant 677C > T: a meta-analysis2007143151726173210.1002/ajmg.a.318122-s2.0-34547678487ZhangT.LouJ.ZhongR.WuJ.ZouL.SunY.LuX.LiuL.MiaoX.XiongG.Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature201384e5957010.1371/journal.pone.00595702-s2.0-84875963812BlomH. J.ShawG. M.Den HeijerM.FinnellR. H.Neural tube defects and folate: case far from closed20067972473110.1038/nrn19862-s2.0-33747588534SafraN.BassukA. G.FergusonP. J.AguilarM.CoulsonR. L.ThomasN.HitchensP. L.DickinsonP. J.VernauK. M.WolfZ. T.BannaschD. L.Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans201397e100364610.1371/journal.pgen.10036462-s2.0-84880798219BassukA. G.MuthuswamyL. B.BolandR.SmithT. L.HulstrandA. M.NorthrupH.HakemanM.DierdorffJ. M.YungC. K.LongA.BrouilletteR. B.AuK. S.GurnettC.HoustonD. W.CornellR. A.ManakJ. R.Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene2013226109711112322301810.1093/hmg/dds5152-s2.0-8487455178123223018GaoY.ChenX.ShangguanS.BaoY.LuX.ZouJ.GuoJ.DaiY.ZhangT.Association study of PARD3 gene polymorphisms with neural tube defects in a Chinese han population201219776477110.1177/19337191114338862-s2.0-84863516472Gonzalez-HerreraL.Martín Cerda-FloresR.Luna-RiveroM.Canto-HerreraJ.Pinto-EscalanteD.Perez-HerreraN.Quintanilla-VegaB.Paraoxonase 1 polymorphisms and haplotypes and the risk for having offspring affected with spina bifida in Southeast Mexico2010881198799410.1002/bdra.207272-s2.0-78649578089LiuJ.WangL.FuY.LiZ.ZhangY.ZhangL.JinL.YeR.RenA.Association between maternal COMT gene polymorphisms and fetal neural tube defects risk in a Chinese population20141001222910.1002/bdra.232082-s2.0-84892882849NarisawaA.KomatsuzakiS.KikuchiA.NiihoriT.AokiY.FujiwaraK.TanemuraM.HataA.SuzukiY.ReltonC. L.GrinhamJ.LeungK.-Y.PartridgeD.RobinsonA.StoneV.GustavssonP.StanierP.CoppA. J.GreeneN. D. E.TominagaT.MatsubaraY.KureS.Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans20122171496150310.1093/hmg/ddr5852-s2.0-84858189393KruppD. R.SoldanoK. L.GarrettM. E.CopeH.Ashley-KochA. E.GregoryS. G.Missing genetic risk in neural tube defects: can exome sequencing yield an insight?2014100864264610.1002/bdra.232762-s2.0-84906486678GilbertS. F.2003Baltimore, Md, USASinauer AssociatesKellerR.Cell migration during gastrulation20051755335411609963810.1016/j.ceb.2005.08.0062-s2.0-2464444573916099638CoppA. J.GreeneN. D. E.MurdochJ. N.The genetic basis of mammalian neurulation20034107847931367987110.1038/nrg11812-s2.0-014148338213679871CoppA. J.BrookF. A.Peter EstibeiroJ.ShumA. S. W.CockroftD. L.The embryonic development of mammalian neural tube defects1990355363403226373610.1016/0301-0082(90)90037-H2-s2.0-00249935622263736GoldenJ. A.ChernoffG. F.Intermittent pattern of neural tube closure in two strains of mice19934717380847546010.1002/tera.14204701122-s2.0-00274618638475460Van AllenM. I.KalousekD. K.ChernoffG. F.JuriloffD.HarrisM.McGillivrayB. C.YongS.-L.LangloisS.MacLeodP. M.ChitayatD.FriedmanJ. M.WilsonR. D.McFaddenD.PantzarJ.RitchieS.HallJ. G.Evidence for multi-site closure of the neural tube in humans1993475723743826700410.1002/ajmg.13204705282-s2.0-00274933648267004O'RahillyR.MüllerF.The two sites of fusion of the neural folds and the two neuropores in the human embryo200265416217010.1002/tera.100072-s2.0-0036130683CoppA. J.BernfieldM.Etiology and pathogenesis of human neural tube defects: insights from mouse models19946662463110.1097/00008480-199412000-000022-s2.0-0028003811DavidsonL. A.KellerR. E.Neural tube closure in Xenopus laevis involves medial migration, directed protrusive activity, cell intercalation and convergent extension199912620454745562-s2.0-0032739204Van StraatenH. W. M.JaskollT.RousseauA. M. J.Terwindt-RouwenhorstE. A. W.GreenbergG.ShankarK.MelnickM.Raphe of the posterior neural tube in the chick embryo: its closure and reopening as studied in living embryos with a high definition light microscope19931981657610.1002/aja.10019801072-s2.0-0027369377ColasJ.-F.SchoenwolfG. C.Subtractive hybridization identifies chick-cripto, a novel EGF-CFC ortholog expressed during gastrulation, neurulation and early cardiogenesis200025522052171102428010.1016/S0378-1119(00)00337-12-s2.0-003468705811024280CoppA. J.GreeneN. D. E.Defining a PARticular pathway of neural tube closure20101811210.1016/j.devcel.2010.01.0022-s2.0-74049119727Ybot-GonzalezP.SaveryD.GerrelliD.SignoreM.MitchellC. E.FauxC. H.GreeneN. D. E.CoppA. J.Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure2007134478979910.1242/dev.0003802-s2.0-33947304005ColasJ.-F.SchoenwolfG. C.Towards a cellular and molecular understanding of neurulation200122121171451137648210.1002/dvdy.11442-s2.0-003501986011376482WallingfordJ. B.FraserS. E.HarlandR. M.Convergent extension: the molecular control of polarized cell movement during embryonic development20022669570610.1016/s1534-5807(02)00197-12-s2.0-0036087024YamaguchiY.ShinotsukaN.NonomuraK.TakemotoK.KuidaK.YosidaH.MiuraM.Live imaging of apoptosis in a novel transgenic mouse highlights its role in neural tube closure201119561047106010.1083/jcb.2011040572-s2.0-84855506461ZohnI. E.ChesnuttC. R.NiswanderL.Cell polarity pathways converge and extend to regulate neural tube closure20031394514541294662210.1016/S0962-8924(03)00173-92-s2.0-014204329312946622KomiyaY.HabasR.Wnt signal transduction pathways200842687510.4161/org.4.2.58512-s2.0-45849117967SmithJ. L.SchoenwolfG. C.Further evidence of extrinsic forces in bending of the neural plate19913072225236185632410.1002/cne.9030702062-s2.0-00259068361856324ShumA. S. W.CoppA. J.Regional differences in morphogenesis of the neuroepithelium suggest multiple mechanisms of spinal neurulation in the mouse19961941657388004242-s2.0-00300075788800424MoranD.RiceR. W.An ultrastructural examination of the role of cell membrane surface coat material during neurulation19756411721814584510.1083/jcb.64.1.1722-s2.0-001643133545845WatermanR. E.SEM observations of surface alterations associated with neural tube closure in the mouse and hamster197518319598118039910.1002/ar.10918301092-s2.0-00167261701180399WatermanR. E.Topographical changes along the neural fold associated with neurulation in the hamster and mouse1976146215117194184710.1002/aja.10014602042-s2.0-0017161224941847RiceR. W.MoranD. J.A scanning electron microscopic and x-ray microanalytic study of cell surface material during amphibian neurulation1977201347147810.1002/jez.14020103142-s2.0-0017527587MakL. L.Ultrastructural studies of amphibian neural fold fusion19786524354467951010.1016/0012-1606(78)90039-82-s2.0-001807833879510SadlerT. W.Distribution of surface coat material on fusing neural folds of mouse embryos during neurulation1978191334534910.1002/ar.10919103072-s2.0-0017893770GeelenJ. A. G.LangmanJ.Ultrastructural observations on closure of the neural tube in the mouse19791561738845355310.1007/BF003157162-s2.0-0018742364453553Smits-Van ProoijeA.PoelmannR.DubbeldamJ.MentinkM.Vermeij-KeersC.The formation of the neural tube in rat embryos, cultured in vitro, studied with teratogens1986324145TakahashiH.HowesR. I.Binding pattern of ferritin-labeled lectins (RCAI and WGA) during neural tube closure in the bantam embryo19861743283288376698510.1007/BF006987782-s2.0-00228865613766985TakahashiH.Changes in peanut lectin binding sites on the neuroectoderm during neural tube formation in the bantam chick embryo19881784353358317789010.1007/BF006986662-s2.0-00236931743177890HolmbergJ.ClarkeD. L.FrisenJ.Regulation of repulsion versus adhesion by different splice forms of an Eph receptor200040868092032061108997410.1038/350415772-s2.0-003462679111089974Abdul-AzizN. M.TurmaineM.GreeneN. D. E.CoppA. J.EphrinA-EphA receptor interactions in mouse spinal neurulation: implications for neural fold fusion200953455956810.1387/ijdb.082777na2-s2.0-68849096101PyrgakiC.TrainorP.HadjantonakisA.-K.NiswanderL.Dynamic imaging of mammalian neural tube closure201034429419472055815310.1016/j.ydbio.2010.06.0102-s2.0-7795527144920558153HarrisM. J.JuriloffD. M.Mini-review: toward understanding mechanisms of genetic neural tube defects in mice199960529230510.1002/(sici)1096-9926(199911)60:5<292::aid-tera10>3.0.co;2-62-s2.0-0033503556DadyA.HavisE.EscriouV.CatalaM.DubandJ.-L.Junctional neurulation: a unique developmental program shaping a discrete region of the spinal cord highly susceptible to neural tube defects20143439132081322110.1523/jneurosci.1850-14.20142-s2.0-84907298265SegalL. S.CzochW.HennrikusW. L.Wade ShraderM.KanevP. M.The spectrum of musculoskeletal problems in lipomyelomeningocele20137651351910.1007/s11832-013-0532-52-s2.0-84890486945MontcouquiolM.CrenshawE. B.IIIKelleyM. W.Noncanonical Wnt signaling and neural polarity2006293633861677659010.1146/annurev.neuro.29.051605.1129332-s2.0-3374836217316776590WallingfordJ. B.HabasR.The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity2005132204421443610.1242/dev.020682-s2.0-27744535862Ybot-GonzalezP.Gaston-MassuetC.GirdlerG.KlingensmithJ.ArkellR.GreeneN. D. E.CoppA. J.Neural plate morhogenesis during mouse neurulation is regulated by antagonism of Bmp signalling200713417320332111769360210.1242/dev.0081772-s2.0-3484889572117693602YamaguchiY.MiuraM.How to form and close the brain: insight into the mechanism of cranial neural tube closure in mammals201370173171318610.1007/s00018-012-1227-72-s2.0-84882448130McDonaldS. L.SilverA.The opposing roles of Wnt-5a in cancer200910122092141960303010.1038/sj.bjc.66051742-s2.0-6765059477119603030KellerR.Shaping the vertebrate body plan by polarized embryonic cell movements20022985600195019541247124710.1126/science.10794782-s2.0-003703282812471247DabdoubA.DonohueM. J.BrennanA.WolfV.MontcouquiolM.SassoonD. A.HseihJ.-C.RubinJ. S.SalinasP. C.KelleyM. W.Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea200313011237523841270265210.1242/dev.004482-s2.0-1244432970812702652GoodrichL. V.StruttD.Principles of planar polarity in animal development201113810187718922152173510.1242/dev.0540802-s2.0-7995556508521521735ShihJ.KellerR.Cell motility driving mediolateral intercalation in explants of Xenopus laevis199211649019142-s2.0-0027082578LoweryL. A.SiveH.Strategies of vertebrate neurulation and a re-evaluation of teleost neural tube formation2004121101189119710.1016/j.mod.2004.04.0222-s2.0-4344663006HarringtonM. J.HongE.BrewsterR.Comparative analysis of neurulation: first impressions do not count2009761095496510.1002/mrd.210852-s2.0-69749109403KleinT. J.MlodzikM.Planar cell polarization: an emerging model points in the right direction20052115517610.1146/annurev.cellbio.21.012704.1328062-s2.0-27744538492MatakatsuH.BlairS. S.Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing200413115378537941524055610.1242/dev.012542-s2.0-444424097215240556CasalJ.LawrenceP. A.StruhlG.Two separate molecular systems, Dachsous/Fat and Starry night/Frizzled, act independently to confer planar cell polarity2006133224561457210.1242/dev.026412-s2.0-33845288905VladarE. K.AnticD.AxelrodJ. D.Planar cell polarity signaling: the developing cell's compass200913a00296410.1101/cshperspect.a0029642-s2.0-70449098259MatisM.AxelrodJ. D.Regulation of PCP by the fat signaling pathway20132720220722202414287310.1101/gad.228098.1132-s2.0-8488592527524142873GubbD.García-BellidoA.A genetic analysis of the determination of cuticular polarity during development in Drosophila melanogaster19826837572-s2.0-0020004250AdlerP. N.TaylorJ.CharltonJ.The domineering non-autonomy of frizzled and Van Gogh clones in the Drosophila wing is a consequence of a disruption in local signaling200096219720710.1016/S0925-4773(00)00392-02-s2.0-0001393236WongL. L.AdlerP. N.Tissue polarity genes of Drosophila regulate the subcellular location for prehair initiation in pupal wing cells19931231209221840819910.1083/jcb.123.1.2092-s2.0-00273611858408199MurdochJ. N.DoudneyK.PaternotteC.CoppA. J.StanierP.Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification20011022259326011170954610.1093/hmg/10.22.25932-s2.0-003588864211709546WangJ.HambletN. S.MarkS.DickinsonM. E.BrinkmanB.SegilN.FraserS. E.ChenP.WallingfordJ. B.Wnyshaw-BorisA.Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation20061339176717781657162710.1242/dev.023472-s2.0-3374454715216571627CurtinJ. A.QuintE.TsipouriV.ArkellR. M.CattanachB.CoppA. J.HendersonD. J.SpurrN.StanierP.FisherE. M.NolanP. M.SteelK. P.BrownS. D. M.GrayI. C.MurdochJ. N.Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse200313131129113310.1016/s0960-9822(03)00374-92-s2.0-10744227509HambletN. S.LijamN.Ruiz-LozanoP.WangJ.YangY.LuoZ.MeiL.ChienK. R.SussmanD. J.Wynshaw-BorisA.Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure200212924582758381242172010.1242/dev.001642-s2.0-003693163312421720EtheridgeS. L.RayS.LiS.HambletN. S.LijamN.TsangM.GreerJ.KardosN.WangJ.SussmanD. J.ChenP.Wynshaw-BorisA.Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development2008411e10002591900895010.1371/journal.pgen.10002592-s2.0-5714911431519008950WangY.GuoN.NathansJ.The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells2006268214721561649544110.1523/JNEUROSCI.4698-05.20052-s2.0-3364563703816495441TorbanE.PatenaudeA.-M.LeclercS.RakowieckiS.GauthierS.AndelfingerG.EpsteinD. J.GrosP.Genetic interaction between members of the Vangl family causes neural tube defects in mice20081059344934541829664210.1073/pnas.07121261052-s2.0-4214919118918296642LuX.BorchersA. G. M.JolicoeurC.RayburnH.BakerJ. C.Tessier-LavigneM.PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates2004430699593981522960310.1038/nature026772-s2.0-304284565515229603MurdochJ. N.HendersonD. J.DoudneyK.Gaston-MassuetC.PhillipsH. M.PaternotteC.ArkellR.StanierP.CoppA. J.Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse200312287981249939010.1093/hmg/ddg0142-s2.0-003743954112499390SuribenR.KivimäeS.FisherD. A. C.MoonR. T.CheyetteB. N. R.Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak200941997798510.1038/ng.4352-s2.0-69349103197PlaczekM.YamadaT.Tessier-LavigneM.JessellT.DoddJ.Control of dorsoventral pattern in vertebrate neural development: induction and polarizing properties of the floor plate199111321051222-s2.0-0026339029PlaczekM.Tessier-LavigneM.YamadaT.JessellT.DoddJ.Mesodermal control of neural cell identity: floor plate induction by the notochord1990250498398598810.1126/science.22374432-s2.0-0025598254YamadaT.PlaczekM.TanakaH.DoddJ.JessellT. M.Control of cell pattern in the developing nervous system: polarizing activity of the floor plate and notochord199164363564710.1016/0092-8674(91)90247-v2-s2.0-0026061044YamadaT.PfaffS. L.EdlundT.JessellT. M.Control of cell pattern in the neural tube: motor neuron induction by diffusible factors from notochord and floor plate199373467368610.1016/0092-8674(93)90248-o2-s2.0-0027256437GouldingM. D.LumsdenA.GrussP.Signals from the notochord and floor plate regulate the region-specific expression of two Pax genes in the developing spinal cord199311731001101681007622-s2.0-00274979818100762EomD. S.AmarnathS.FogelJ. L.AgarwalaS.Bone morphogenetic proteins regulate hinge point formation during neural tube closure by dynamic modulation of apicobasal polarity2012941080481610.1002/bdra.230522-s2.0-84867679532van StraatenH. W. M.HekkingJ. W. M.Wiertz-HoesselsE. J. L. M.ThorsF.DrukkerJ.Effect of the notochord on the differentiation of a floor plate area in the neural tube of the chick embryo19881774317324335484710.1007/BF003158392-s2.0-00239029213354847van StraatenH. W. M.HekkingJ. W. M.ThorsF.Wiertz-HoesselsE. L.DrukkerJ.Induction of an additional floor plate in the neural tube1985232919738347772-s2.0-00224063473834777SmithJ. L.SchoenwolfG. C.Notochordal induction of cell wedging in the chick neural plate and its role in neural tube formation198925014962272361010.1002/jez.14025001072-s2.0-00245931332723610Ybot-GonzalezP.CogramP.GerrelliD.CoppA. J.Sonic hedgehog and the molecular regulation of mouse neural tube closure20021291025072517119732812-s2.0-003633337311973281LiemK. F.Jr.JessellT. M.BriscoeJ.Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites200012722485548662-s2.0-0033637101GreeneN. D. E.CoppA. J.Development of the vertebrate central nervous system: formation of the neural tube200929430331110.1002/pd.22062-s2.0-64849104728McShaneS. G.MolèM. A.SaveryD.GreeneN. D. E.TamP. P. L.CoppA. J.Cellular basis of neuroepithelial bending during mouse spinal neural tube closure2015404211312410.1016/j.ydbio.2015.06.0032-s2.0-84937739213Ybot-GonzalezP.Gaston-MassuetC.GirdlerG.KlingensmithJ.ArkellR.GreeneN. D. E.CoppA. J.Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling2007134173203321110.1242/dev.0081772-s2.0-34848895721McMahonJ. A.TakadaS.ZimmermanL. B.FanC.-M.HarlandR. M.McMahonA. P.Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite199812101438145210.1101/gad.12.10.14382-s2.0-0032523777StottmannR. W.BerrongM.MattaK.ChoiM.KlingensmithJ.The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms200629526476631671283610.1016/j.ydbio.2006.03.0512-s2.0-3374528061116712836GroppeJ.GreenwaldJ.WiaterE.Rodriguez-LeonJ.EconomidesA. N.KwiatkowskiW.AffolterM.ValeW. W.Izpisua BelmonteJ. C.ChoeS.Structural basis of BMP signalling inhibition by the cystine knot protein Noggin200242069166366421247828510.1038/nature012452-s2.0-003706965312478285BrunetL. J.McMahonJ. A.McMahonA. P.HarlandR. M.Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton1998280536814551457960373810.1126/science.280.5368.14552-s2.0-00325772769603738LaurikkalaJ.KassaiY.PakkasjärviL.ThesleffI.ItohN.Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot20032641911051462323410.1016/j.ydbio.2003.08.0112-s2.0-024252129714623234YipG. W.FerrettiP.CoppA. J.Heparan sulphate proteoglycans and spinal neurulation in the mouse embryo2002129921092119119598212-s2.0-003633355811959821CirunaB.RossantJ.FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak200111374910.1016/s1534-5807(01)00017-x2-s2.0-0035408007TakadaS.StarkK. L.SheaM. J.VassilevaG.McMahonJ. A.McMahonA. P.Wnt-3a regulates somite and tailbud formation in the mouse embryo199482174189829993710.1101/gad.8.2.1742-s2.0-00281573928299937NiederreitherK.SubbarayanV.DolléP.ChambonP.Embryonic retinoic acid synthesis is essential for early mouse post-implantation development199921444444810.1038/77882-s2.0-0032958632HungC. F.HsuH. K.LinK. R.SEM observations of the neural fold associated with neurulation in the rat19861042872902-s2.0-0022789089LawsonA.EnglandM. A.Neural fold fusion in the cranial region of the chick embryo1998212447348110.1002/(SICI)1097-0177(199808)212:4<473::AID-AJA1>3.0.CO;2-E2-s2.0-0031880491Van StraatenH. W. M.PeetersM. C. E.SzpakK. F. W.HekkingJ. W. M.Initial closure of the mesencephalic neural groove in the chick embryo involves a releasing zipping-up mechanism1997209433334110.1002/(sici)1097-0177(199708)209:4<333::aid-aja1>3.0.co;2-j2-s2.0-0030833865CirunaB.JennyA.LeeD.MlodzikM.SchierA. F.Planar cell polarity signalling couples cell division and morphogenesis during neurulation200643970732202241640795310.1038/nature043752-s2.0-3054443900616407953RashidD.NewellK.ShamaL.BradleyR.A requirement for NF-protocadherin and TAF1/Set in cell adhesion and neural tube formation200629111701811642660210.1016/j.ydbio.2005.12.0272-s2.0-3364477952516426602DavidsonL. A.EzinA. M.KellerR.Embryonic wound healing by apical contraction and ingression in Xenopus laevis20025331631761221109910.1002/cm.100702-s2.0-003683784512211099BrounsM. R.MathesonS. F.HuK.-Q.DelalleI.CavinessV.S. J.SilverJ.BronsonR. T.SettlemanJ.The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development200012722489149032-s2.0-0033636507de DiegoI.KyriakopoulouK.KaragogeosD.WassefM.Multiple influences on the migration of precerebellar neurons in the caudal medulla20021292297306118070232-s2.0-003633734311807023KellerR.Mechanisms of elongation in embryogenesis200613312229123021672087410.1242/dev.024062-s2.0-3374590862116720874HackettD. A.SmithJ. L.SchoenwolfG. C.Epidermal ectoderm is required for full elevation and for convergence during bending of the avian neural plate1997210439740610.1002/(sici)1097-0177(199712)210:4<397::aid-aja4>3.0.co;2-b2-s2.0-0030657634HaigoS. L.HildebrandJ. D.HarlandR. M.WallingfordJ. B.Shroom induces apical constriction and is required for hingepoint formation during neural tube closure200313242125213710.1016/j.cub.2003.11.0542-s2.0-0346403360BaillyM.Connecting cell adhesion to the actin polymerization machinery: vinculin as the missing link?200313416316510.1016/s0962-8924(03)00030-82-s2.0-0037377222AnderssonE.BryjovaL.BirisK.YamaguchiT. P.ArenasE.BryjaV.Genetic interaction between Lrp6 and Wnt5a during mouse development201023912372451979551210.1002/dvdy.221012-s2.0-7394915547719795512MiróX.ZhouX.BoretiusS.MichaelisT.KubischC.Alvarez-BoladoG.GrussP.Haploinsufficiency of the murine polycomb gene Suz12 results in diverse malformations of the brain and neural tube200927-841241810.1242/dmm.0016022-s2.0-70349774670MagnaghiP.RobertsC.LorainS.LipinskiM.ScamblerP. J.HIRA, a mammalian homologue of saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax319982017477973153610.1038/17392-s2.0-00317136669731536PirityM. K.WangW.-L.WolfL. V.TammE. R.Schreiber-AgusN.CveklA.Rybp, a polycomb complex-associated protein, is required for mouse eye development20077, article 3910.1186/1471-213x-7-392-s2.0-34249088330FujiiK.Primary cilia and hedgehog signaling201547259265GoumyC.Gay-BellileM.Eymard-PierreE.KemenyS.GouasL.DéchelotteP.GallotD.VéronèseL.TchirkovA.Pebrel-RichardC.VagoP.De novo 2q36.1q36.3 interstitial deletion involving the PAX3 and EPHA4 genes in a fetus with spina bifida and cleft palate2014100650751110.1002/bdra.232462-s2.0-84903123220SchubertF. R.TremblayP.MansouriA.FaisstA. M.KammandelB.LumsdenA.GrussP.DietrichS.Early mesodermal phenotypes in Splotch suggest a role for Pax3 in the formation of epithelial somites200122235065211174708410.1002/dvdy.12112-s2.0-003476129711747084RoudgariH.FarndonP. A.MurrayA. D.HardyC.MiedzybrodzkaZ.Is PATCHED an important candidate gene for neural tube defects? Cranial and thoracic neural tube defects in a family with Gorlin syndrome: a case report2012821717610.1111/j.1399-0004.2011.01725.x2-s2.0-84862268605LuoJ.BalkinN.StewartJ. F.SarwarkJ. F.CharrowJ.NyeJ. S.Neural tube defects and the 13q deletion syndrome: evidence for a critical region in 13q33-34200091322723010.1002/(sici)1096-8628(20000320)91:3<227::aid-ajmg14>3.0.co;2-i2-s2.0-0034105691RodríguezL.PérezI. C.MontesJ. H.JareñoM. L. L.GrondonaF. L.Martínez-FríasM. L.Terminal deletion of the chromosome 7(q36-qter) in an infant with sacral agenesis and anterior myelomeningocele20021101737710.1002/ajmg.103652-s2.0-0036605109