Abstract
Neural tube defects (NTDs), including spina bifida and anencephaly, represent the most severe and common malformations of the central nervous system affecting 0.7–3 per 1000 live births. They result from the failure of neural tube closure during the first few weeks of pregnancy. They have a complex etiology that implicate a large number of genetic and environmental factors that remain largely undetermined. Extensive studies in vertebrate models have strongly implicated the non-canonical Wnt/planar cell polarity (PCP) signaling pathway in the pathogenesis of NTDs. The defects in this pathway lead to a defective convergent extension that is a major morphogenetic process essential for neural tube elongation and subsequent closure. A large number of genetic studies in human NTDs have demonstrated an important role of PCP signaling in their etiology. However, the relative contribution of this pathway to this complex etiology awaits a better picture of the complete genetic architecture of these defects. The emergence of new genome technologies and bioinformatics pipelines, complemented with the powerful tool of animal models for variant interpretation as well as significant collaborative efforts, will help to dissect the complex genetics of NTDs. The ultimate goal is to develop better preventive and counseling strategies for families affected by these devastating conditions.
Highlights
Neural tube defects (NTDs) result from the failure of the neural tube closure during weeks 3–5 after fertilization [1,2]
The first process that was shown to be mediated by the non-canonical Wnt/planar cell polarity (PCP) signaling in vertebrates was the convergent extension during gastrulation and neurulation in Xenopus and zebrafish
This study identified double damaging variants in CELSR genes and other PCP genes in 3.3% of their cohort and demonstrated a combined effect of two heterozygous variants of CELSR2 and DVL3 in down regulation of PCP signaling in vitro
Summary
Neural tube defects (NTDs) result from the failure of the neural tube closure during weeks 3–5 after fertilization [1,2]. The two most common forms of open NTDs are anencephaly and myelomeningocele (MMC) The former results from the failure of the neural tube closure at the cranial region, while the latter at the spinal region. The focus is placed on the process of convergent extension that is mediated by PCP signaling and that is the major force underlying the elongation and narrowing of the neural tube This is followed by a summary of the undebatable evidence of an important role of defective. The last step of NT closure is fusion of the opposing tips of the neural folds and the separation of the closed NT from the overlying non-neural ectoderm which later develops into the epidermis (Figure 1A) This step involves significant tissue remodeling and dynamic behaviors including the formation of cellular bridges, ruffles, filopodia and lamellipodia [20]. Fate mapping studies in chick embryos suggested similar cellular or molecular mechanisms to primary neurulation [28]
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