Genetics and development of neural tube defects

Abstract

Congenital defects of neural tube closure (neural tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (eg anencephaly, spina bifida) varying depending on the region of neural tube that remains open. While mutation of > 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasizes the importance of gene-gene and gene-environment interactions in the origins of these defects. A number of cell biological functions are essential for neural tube closure, with defects of the cytoskeleton, cell cycle and molecular regulation of cell viability prominent among the mouse NTD mutants. Many transcriptional regulators and proteins that affect chromatin structure are also required for neural tube closure, although the downstream molecular pathways regulated by these proteins is unknown. Some key signalling pathways for NTDs have been identified: over-activation of sonic hedgehog signalling and loss of function in the planar cell polarity (non-canonical Wnt) pathway are potent causes of NTD, with requirements also for retinoid and inositol signalling. Folic acid supplementation is an effective method for primary prevention of a proportion of NTDs in both humans and mice, although the embryonic mechanism of folate action remains unclear. Folic acid-resistant cases can be prevented by inositol supplementation in mice, raising the possibility that this could lead to an additional preventive strategy for human NTDs in future.

Figure 1. Diagrammatic representation of neural tube closure and the origin of NTDs in (A) mouse and (B) human embryos.

Initiation events (Closures 1, 2, 3) and completion events (at ‘neuropores’) are joined by unidirectional or bidirectional neural tube zippering (blue arrows). The affected events leading to NTDs (red labels) are indicated by red arrows. Secondary neurulation proceeds from the level of the closed posterior neuropore, as a result of canalisation within the tail bud (green). Modified from [6][64].

Figure 2. Molecular regulation of dorsolateral bending in mouse neural tube closure

Neural tube closure changes in morphology from (A) high spinal to (B) low spinal regions of the mouse embryo. In the upper spine, the neural plate bends solely in the midline, at the median hinge point (MHP), whereas in the low spine bending occurs at dorsolateral hinge points (DLHPs). (C) Summary of the molecular interactions regulating DLHP formation. In the upper spine, DLHPs are absent because of unopposed inhibition by BMP2. Although Noggin expression is stimulated by BMP2 at all levels of the body axis, Shh expression from the notochord is strong in the upper spine, inhibiting Noggin. In the lower spine, Shh influence is reduced, Noggin expression is de-inhibited and antagonises the inhibitory influence of BMP2, allowing DLHPs to form. Yellow triangles: MHP; red triangles: DLHPs; green arrows: stimulatory interactions; red lines: inhibitory interactions; dashed lines: inactive influences. Modified from [65]