Neural tube closure and neural tube defects: Studies in animal models reveal known knowns and known unknowns

Abstract

The vertebrate central nervous system is a hollow structure that develops first as a flat sheet of cells and subsequently rolls into a tube during embryogenesis. Failure of this rolling process, called neural tube closure, results in a class of common human birth defects called neural tube defects. The cellular and molecular mechanisms governing neural tube closure have been studied extensively in animal models, but much remains to be elucidated. In this review, I will highlight recent progress in understanding neural tube closure mechanisms and how these studies can inform our search for the genes that underlie human neural tube defects. Supplementary material for this article can be found on the American Journal of Medical Genetics (Part C) website (http://www.mrw.interscience.wiley.com/suppmat/1552-4868/suppmat/2005/135/v135.1.wallingford.html)

Comparative analysis of neurulation: First impressions do not count

“…A more detailed discussion of the cellular events of neurulation can be obtained in several excellent reviews (Colas and Schoenwolf, 2001;Lowery and Sive, 2004;Wallingford, 2005;Clarke, 2009). At a morphological level, primary neurulation can be described as the bending and folding of the neural plate, a flat and thickened epithelial layer on the dorsal surface of the embryo, to form a hollowed NT.…”

“…Bending is accomplished by furrowing (the formation of hinge points; a single median hinge point above the prechordal plate and notochord; and paired dorsolateral hinge points present principally at future brain levels) and folding (the rotation of the neural plate around hinge points; Fig. 3A,A.1; Shum and Copp, 1996;Smith and Schoenwolf, 1997;Colas and Schoenwolf, 2001;Lowery and Sive, 2004;Wallingford, 2005). The rostrocaudal level at which bending is initiated varies amongst species.…”

“…3A.1 and A.2). Apical constriction is thought to involve a contractile ring at the apical pole of neuroepithelial cells, although other models have also been proposed (Wallingford, 2005). Genes implicated in hinge point formation include p190RhoGAP and shroom, which encode a negative regulator of Rho GTPase and an actin-binding protein, respectively (Brouns et al, 2000;Martin, 2004).…”

“…3C,C.1; Schroeder, 1971;Haigo et al, 2003). As in mice, this process is mediated by the actinbinding protein Shroom and disruption of Shroom function results in a specific failure of hinge point formation and brain NTDs (Haigo et al, 2003;Martin, 2004;Wallingford, 2005;Lee et al, 2007). Further shaping and closure of the NT involves a number of complex cell movements.…”

“…Moreover, cells in the deep layer have a columnar (elongated) shape and maintain their relative medio-lateral position throughout neurulation (Papan and Campos-Ortega, 1994;Hong and Brewster, 2006). In Xenopus, cells in the superficial layer undergo apical constriction (Haigo et al, 2003;Wallingford, 2005), an epithelial cell property. Thus, both early zebrafish and Xenopus neuroepithelial cells appear hybrid in terms of their properties.…”