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  • Review Article
  • Published:

A gene regulatory network orchestrates neural crest formation

Nature Reviews Molecular Cell Biology volume 9, pages 557–568 (2008)Cite this article

Key Points

  • The neural crest (NC) is a multipotent, migratory cell population that is unique to vertebrate embryos and that forms numerous derivatives ranging from melanocytes, peripheral neurons and glia, to bone and cartilage of the face. A multimodule gene regulatory network mediates the complex process of NC formation, involving signalling events and upregulation of transcription factors that regulate one another and effector genes that are involved in migration and differentiation.

  • Initial induction of the NC occurs at the neural plate border of the gastrula and is mediated by the combination of Wnt, bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signalling. These signals control the gene expression of transcription factors, such as Msx1, Msx2, Zic1, Pax3 and Pax7, which establish the competence of the neural plate border territory to respond to NC inducing signals.

  • Neural plate border genes in turn regulate NC specifier genes that maintain the NC progenitor pool by controlling the cell cycle, conferring survival properties to newly induced NC cells, controlling their emigration from the neural tube and migration along well-established pathways, and by regulating cell-fate decisions and events of terminal differentiation.

  • Bona fide NC cells delaminate from the neural tube once they have undergone an epithelial to mesenchymal transition and then embark on extensive migrations to sometimes distant sites in the periphery, where they settle and differentiate into various derivatives. NC specifier genes are thought to directly control these events by regulating various downstream-effector genes.

  • NC cells interact with and modify their environments during migration. They respond to diverse guidance cues, including ephrins and semaphorins, that help define their migratory pathways.

  • The NC gene regulatory network underlying the complex process of NC formation was present in the last common ancestor of jawless and jawed vertebrates and has been tightly conserved for over 500 million years.

Abstract

The neural crest is a multipotent, migratory cell population that is unique to vertebrate embryos and gives rise to many derivatives, ranging from the peripheral nervous system to the craniofacial skeleton and pigment cells. A multimodule gene regulatory network mediates the complex process of neural crest formation, which involves the early induction and maintenance of the precursor pool, emigration of the neural crest progenitors from the neural tube via an epithelial to mesenchymal transition, migration of progenitor cells along distinct pathways and overt differentiation into diverse cell types. Here, we review our current understanding of these processes and discuss the molecular players that are involved in the neural crest gene regulatory network.

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Figure 1: Regulatory steps in neural crest formation.
Figure 2: Neural crest specification.

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Acknowledgements

We thank S. Bhattacharyya and N. Nikitina for their suggestions and critical reading of the manuscript. This work was supported by California Institute for Regenerative Medicine (CIRM) fellowship to T.S.S. and National Institute of Health (NIH) grants, DE017919 and NS36585, to M.B.F.

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    Tatjana Sauka-Spengler & Marianne Bronner-Fraser

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Glossary

Synapomorphy

A derived or specialized characteristic that is shared by two or more groups of organisms and that was present in their last common ancestor and can be used to establish phylogenies.

Gastrulation

A series of morphogenetic movements that is observed during the early development of all triploblast animals. It leads to the formation of a multilayered embryo with an outer cell layer (ectoderm), an inner cell layer (endoderm) and an intermediate cell layer (mesoderm).

Neurulation

A morphogenetic process during which the progenitors of the nervous system segregate from the ectoderm. During neurulation, a flat sheet of thickened ectoderm (neural plate) is transformed into the rudiment of central nervous system, the neural tube.

Metalloprotease

A peptidase that depends on a coordinated metal ion (Zn2+) for its catalytic activity. These proteinases have an important role not only in extracellular matrix remodelling and degradation, but also in programmed cell death, cell proliferation and differentiation.

Paraxial mesoderm

Most dorsal region of the embryonic mesoderm in vertebrate embryos. After segmentation it forms paired somites that ultimately give rise to axial skeleton and skeletal muscles.

Animal cap assay

An assay to test the effects of selected regulatory factors in 'naive' cells. Factors are introduced into fertilized eggs and the animal region of the frog embryo at the blastula stage is dissected off and assayed for response. Conversely, dissected tissue can be directly treated with secreted factors or their inhibitors.

Preplacodal ectoderm

A unique region of the embryonic ectoderm in the future head territory in vertebrate embryos. It contains precursors of all cranial placodes that ultimately contribute to sense organs and cranial sensory ganglia.

Rohon-Beard primary neuron

A large transient sensory neuron that is located in the dorsal aspect of the neural tube in lower vertebrates. It is present in the embryo and in early larval stages, but subsequently disappears.

Epithelial to mesenchymal transition

The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.

Stress fibre

A component of the actin cytoskeleton that consists of contractile bundles of actin and myosin II, which terminate in adhesion plaques that link the actin cytoskeleton to the cell surface. Stress fibres are involved in cell adhesion and the generation of tensile force.

Delamination

Physical dissociation of NC cells from the neuroepithelium in the dorsal aspect of the neural tube. This process requires NC cells to lose their apicobasal polarity and also requires disassembly of the basement membranes, through which NC cells penetrate.

Branchial arches

(also known as pharyngeal arches). A series of bilateral outpouchings on each side of the developing pharynx and mouth cavity in the vertebrate embryo. Differentiated arches typically consist of pharyngeal clefts derived from ectoderm, pharyngeal pouches derived from endoderm and a bony or cartilaginous rod of neural crest origin.

Adherens junction

A specialized intercellular junction of the plasma membrane in which cadherin molecules of adjacent cells interact in a Ca2+-dependent manner. Actin filaments are linked to this structure through catenins that are located underneath the junction.

Tight junction

A circumferential ring at the apex of epithelial cells that seals adjacent cells to one another. Tight junctions function as selective (semi-permeable) diffusion barriers and regulate solute and ion flux between adjacent epithelial cells.

Gap junction

A communicating junction (permeable to molecules up to 1 kDa) that exists between adjacent cells. Gap junctions are composed of 12 connexin protein subunits, 6 of which form a connexon or hemichannel that is contributed to by each of the coupled cells.

Somite

A series of paired blocks of mesodermal cells that form during early vertebrate development and that give rise to the backbone and body muscle.

Dermomyotome

An epithelial cell layer that forms the dorsolateral region of the somite that faces the ectoderm and further differentiates into the most dorsal dermatome, which later differentiates into dermis and myotome — future skeletal muscles.

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Sauka-Spengler, T., Bronner-Fraser, M. A gene regulatory network orchestrates neural crest formation. Nat Rev Mol Cell Biol 9, 557–568 (2008). https://doi.org/10.1038/nrm2428

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