Abstract
The human neural tube defects (NTD), anencephaly, spina bifida and craniorachischisis, originate from a failure of the embryonic neural tube to close. Human NTD are relatively common and both complex and heterogeneous in genetic origin, but the genetic variants and developmental mechanisms are largely unknown. Here we review the numerous studies, mainly in mice, of normal neural tube closure, the mechanisms of failure caused by specific gene mutations, and the evolution of the vertebrate cranial neural tube and its genetic processes, seeking insights into the etiology of human NTD. We find evidence of many regions along the anterior–posterior axis each differing in some aspect of neural tube closure—morphology, cell behavior, specific genes required—and conclude that the etiology of NTD is likely to be partly specific to the anterior–posterior location of the defect and also genetically heterogeneous. We revisit the hypotheses explaining the excess of females among cranial NTD cases in mice and humans and new developments in understanding the role of the folate pathway in NTD. Finally, we demonstrate that evidence from mouse mutants strongly supports the search for digenic or oligogenic etiology in human NTD of all types.
Highlights
The mechanisms of closure of the neural tube and the development of neural tube closure defects (NTD) are genetically complex and diverse
Studies of mouse embryos have demonstrated that different regions along the anterior–posterior axis have different major mechanisms for bending the neuroepithelium to meet in the midline and differ in fusion mechanisms (Table 2). These reflect several factors [5,6] including the early spinal role of planar cell polarity, the timing of anterior–posterior development of the notochord relative to closure, a gradient of Sonic hedgehog (Shh) signaling along the anterior to posterior spine [22], presence of medial hinge point (MHP) and dorsolateral hinge point (DLHP), differences in expression domains along the anterior–posterior axis of various genes important to closure, such as the Grhl gene family [41] and the Ephrin/Ephrin receptor tyrosine kinases (Ephs) gene families [40,42,43], types of cell projections, cell types that initiate fusion, and factors in the molecular genetics of closure that are unique to the cranial region, such as the dynamics of the actomyosin cytoskeleton
Shared by anencephaly and lumbosacral spina bifida aperta, we suggest these latter families may be enriched for defects in genes that affect DLHP, which can inform the genetic approaches to unraveling some of the genetic complexity of human NTD
Summary
The mechanisms of closure of the neural tube and the development of neural tube closure defects (NTD) are genetically complex and diverse. We give considerable emphasis to the anterior–posterior regional differences in the mechanisms of neural tube closure at the morphological and molecular levels, underlining the concept that defects of closure of the neural tube are mechanistically heterogeneous with distinct or partially overlapping etiologies This heterogeneity predicts genetic differences in the etiologies of human NTD located at different sites along the anterior–posterior axis, as well as genetic heterogeneity at any given site. We focus on cranial neural tube development, its genetic mechanisms of failure to close, and the evolutionary New Head hypothesis that predicts consequential differences between the cranial and spinal regions in the mechanisms of neural tube closure. These differences should inform genetic studies of human NTD. Or clinically, they are often included in NTD, but they are not within the scope of the etiology of failure to form a closed neural tube [6,13]
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