The genetic basis of mammalian neurulation

Key Points Neurulation is a well-known morphogenetic event of embryonic development that has important clinical consequences. The failure of neural tube closure leads to a group of common and severe malformations that are called neural tube defects (NTDs). Although the morphology and cell biology of neurulation are well described, the underlying molecular mechanisms remain poorly understood. More than 80 mutant mouse genes disrupt neurulation and lead to the development of NTDs. Analysis of these mutants allows an in-depth analysis of the developmental mechanisms that underlie neurulation. This review identifies the main categories of genes that are required for each successive event of neurulation, and relates these functional gene groups to probable neurulation mechanisms. Crucial molecular mechanisms of neurulation include the planar cell-polarity pathway, which is essential for the initiation of neural tube closure, and the sonic hedgehog signalling pathway, which regulates neural plate bending in the spinal region and probably also in the brain. Other developmental mechanisms seem to be essential solely for cranial neurulation. These include contraction of apical actin microfilaments, emigration of the cranial neural crest, precisely regulated programmed cell death and a balance between neuroepithelial cell proliferation and differentiation. The mutant mice also offer an opportunity to unravel the mechanisms by which folic acid prevents NTDs, and to develop new therapies for folate-resistant defects. NTDs in some mutant mouse strains can be prevented by folic acid, whereas, in one particular strain, folate is ineffective but inositol can prevent NTDs. More than 80 mutant mouse genes disrupt neurulation and allow an in-depth analysis of the underlying developmental mechanisms. Although many of the genetic mutants have been studied in only rudimentary detail, several molecular pathways can already be identified as crucial for normal neurulation. These include the planar cell-polarity pathway, which is required for the initiation of neural tube closure, and the sonic hedgehog signalling pathway that regulates neural plate bending. Mutant mice also offer an opportunity to unravel the mechanisms by which folic acid prevents neural tube defects, and to develop new therapies for folate-resistant defects.