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  • Review Article
  • Published:

The genetic basis of mammalian neurulation

Nature Reviews Genetics volume 4, pages 784–793 (2003)Cite this article

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.

Abstract

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.

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Figure 1: The rostro-caudal sequence of neurulation events in the mouse embryo.
Figure 2: Mouse fetuses with neural tube defects.
Figure 3: Shaping of the neural plate at the onset of mouse neural tube closure.
Figure 4: Transition in the morphology of neurulation along the developing spine, as seen in schematic transverse section.
Figure 5: Adhesion, fusion and remodelling of the midline at completion of neural tube closure.
Figure 6: Schematic summary of cranial neurulation as exemplified by neural tube closure in the midbrain region.

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Acknowledgements

The authors' research is supported by the Wellcome Trust, the Medical Research Council, the Birth Defects Foundation and Sport Aiding Research in Kids (SPARKS).

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Authors and Affiliations

  1. Neural Development Unit, Institute of Child Health, University College London, London, WC1N 1EH, UK

    Andrew J. Copp & Nicholas D. E. Greene

  2. MRC Mammalian Genetics Unit, Harwell, OX11 0RD, Oxfordshire, UK

    Jennifer N. Murdoch

Authors
  1. Andrew J. Copp
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  2. Nicholas D. E. Greene
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  3. Jennifer N. Murdoch
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Correspondence to Andrew J. Copp.

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DATABASES

FlyBase

stan

Vang

LocusLink

Abl

Apaf1

ApoB

Arg

Bcl10

Cart1

Casp9

Cdh2

Celsr1

Chuk

Csk

ct

Enah

Gcm1

Gli1

Gli2

Gli3

Hes1

Hes3

Ikbkb

Mapk8

Mapk9

Mdm4

Msx1

Mtr

Ncam

Notch3

Numb

Pax3

Pfn1

Ptc1

Rab23

Scrb1

Shh

Tcof1

Tulp1

Twist

Wnt3a

OMIM

anencephaly

spina bifida

ZFIN

tri

Glossary

ECTODERM

The outer of the three embryonic (germ) layers that gives rise to the entire central nervous system, plus other organs and embryonic structures.

NEURAL CREST

A migratory cell population that arises from the midline of the neural tube, which gives rise to a range of cell types in the developing embryo.

ROSTRAL

The front end of the body axis of the developing embryo.

CAUDAL

The tail end of the body axis of the developing embryo.

TAIL BUD

The population of stem cells at the extreme caudal end of the embryo that contains the progenitor cells for formation of the lowest levels of the body axis.

NEUROPORE

A transient 'hole-like' opening in the neural tube at which neural tube closure is undergoing completion.

PRIMITIVE STREAK

The structure in the gastrulation-stage embryo at which ectoderm to mesoderm transformation occurs, with epithelium to mesenchyme transformation.

NOTOCHORD

The rod-like mesodermal structure that extends the length of the body axis, beneath the neural tube of vertebrate embryos.

SOMITES

Segmented blocks of mesoderm on either side of the neural tube in vertebrate embryos.

ORTHOLOGUE

A gene that is the evolutionary counterpart of a similar gene in another species.

MEDIAN HINGE POINT

(MHP). A single midline bending point in the closing neural tube.

NEURAXIS

The developing central nervous system and its main subdivisions, both in the developing brain (forebrain, midbrain and hindbrain) and the spinal cord (cervical, thoracic, lumbar, sacral and caudal/coccygeal).

DORSOLATERAL HINGE POINT

(DLHP). Paired bending points in the dorsolateral region of the closing neural tube.

EPHRINS

A family of cell-surface ligands that interact with a family of cell-surface receptor tyrosine kinases (Eph receptors), which is implicated in the interaction of cell types and the mediation of chemorepulsion and cell adhesion.

GLYCOSYLPHOSPHATIDYLINOSITOL (GPI) ANCHORS

Inositol-containing linkages that tether some proteins (for example, ephrins) to the cell surface.

PARAXIAL MESODERM

The unsegmented mesoderm of the caudal embryonic region that subsequently becomes segmented into somites.

HYALURONAN

A high molecular weight polysaccharide of repeating N-acetyl glucosamine and glucuronic-acid residues that is included among the proteoglycans (which are proteins that comprise a peptide backbone with abundant glycosaminoglycan side chains), although it does not have a protein backbone.

CHONDROITIN SULPHATE

A glycosaminoglycan of repeating N-acetyl-galactosamine and glucuronic-acid residues that forms part of some proteoglycan molecules.

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Copp, A., Greene, N. & Murdoch, J. The genetic basis of mammalian neurulation. Nat Rev Genet 4, 784–793 (2003). https://doi.org/10.1038/nrg1181

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