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  • Review Article
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Neural crest specification: migrating into genomics

Nature Reviews Neuroscience volume 4, pages 795–805 (2003)Cite this article

Key Points

  • Neural crest cells migrate from the neural tube to colonize the far reaches of the embryo, where they form peripheral neurons, glia, connective tissue, bone, secretory cells and the outflow tract of the heart. This article provides an overview of early neural crest development, and discusses how genomic techniques are helping us to understand this process at the genetic level.

  • During neurulation, the neural plate border bends to form the neural folds, which become the dorsal aspect of the neural tube. Depending on the organism and the axial level, neural crest cells initiate migration from the closing neural folds or the dorsal neural tube. Although the neural folds are viewed as 'premigratory' neural crest, only a fraction of these cells will actually migrate.

  • Wnt proteins, bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) mimic the tissue interactions that induce neural crest. The main neural crest-inducing signal from the non-neural ectoderm seems to be a Wnt protein, although the Wnts, BMPs and FGFs might have different roles in neural crest induction and maintenance in different species.

  • Less is known about the events downstream of the signals that induce neural crest, although a growing list of genes has been found to be necessary and/or sufficient to initiate neural crest development. This list includes epidermal, neural and neural crest markers. The relationships between these genes are not clear.

  • Many neural crest genes stimulate proliferation and prevent differentiation (Zic genes, Pax3, c-Myc, Ap2, Msx1 and Msx2, Id2, Notch1 and Twist) or maintain stem cell potential (Foxd3 and Sox10). They include genes for transcriptional repressors (Slug/Snail, Zic1, Msx1 and Msx2, Nbx and Id2) and activators (Sox9 and Sox10, Pax3, c-Myc, Ap2 and Notch1).

  • Genomic level screens could potentially identify all the genes that are involved in early neural crest development, which could then be assembled into functional networks. In chick and Xenopus, it is possible to combine powerful array technologies with experimental embryology, and equally enticing is the intersection of genetics, transgenics and genomics in zebrafish.

Abstract

The bones in your face, the pigment in your skin and the neural circuitry that controls your digestive tract have one thing in common: they are all derived from neural crest cells. The formation of these migratory multipotent cells poses an interesting developmental problem, as neural crest cells are not a distinct cell type until they migrate away from the central nervous system. What defines the pool of cells with neural crest potential, and why do only some of these cells become migratory? New genomic approaches in chick, zebrafish and Xenopus might hold the key.

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Figure 1: Border induction and neurulation.
Figure 2: The current status of a neural crest gene regulatory network.
Figure 3: Integrating embryology and genomics to define a neural crest gene regulatory network.

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Acknowledgements

The authors would like to thank S. Fraser, M. García-Castro, V. Lee, Y. Marahrens and L. Ziemer for critical comments on the manuscript, and the Bronner-Fraser lab for insightful discussions. L.S.G. is supported by a K22 Career Transition Award from the NIH. Work in M.B.F.'s lab is supported, in part, by grants from NIH and NASA.

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Authors and Affiliations

  1. Division of Biology 139-74, California Institute of Technology, Pasadena, 91125, California, USA

    Laura S. Gammill & Marianne Bronner-Fraser

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  1. Laura S. Gammill
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DATABASES

LocusLink

Ap2

BMPs

β-catenin

cadherin-6

CBP

Cited2

claudins

Crestin

Delta

Dlx5

E-cadherin

FGFs

Foxa

Foxd3

Id2

Mdm2

Msx1

Msx2

Msxb

Msxc

c-Myc

N-cadherin

Ngn1

Noelin

Notch1

Occludin

p300

Pax3

Pax7

Rhob

Slug

Snail

Sox9

Sox10

Twist

Wnts

Zic1

Zic2

Zic3

Zic5

Xenbase

nbx

TIGR Gallus gallus Gene Index

Chordin

Noggin

TIGR Xenopus laevis Gene Index

eif4a2

Meis1b

Zicr1

http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=11771

Glossary

WNT PROTEINS

A family of highly conserved secreted signalling molecules, which are related to the Drosophila wingless protein and regulate cell–cell interactions during embryogenesis. Wnt proteins bind on the cell surface to receptors of the Frizzled family.

BONE MORPHOGENETIC PROTEINS

(BMPs). Multifunctional secreted proteins of the transforming growth factor-β superfamily. In the early embryo, they participate in dorsoventral patterning.

FIBROBLAST GROWTH FACTORS

(FGFs). Multifunctional factors that are involved in embryonic development. More than 20 FGFs and 4 FGF receptors have been described. Their coordinated activity controls cell proliferation, migration, survival and differentiation. FGFs regulate growth and morphogenesis by an early action on regional patterning, and a later effect on the growth of progenitor cells of the forebrain.

ANAMNIOTES

Vertebrates, such as fish and amphibians, that do not develop inside an amnion.

ZINC FINGER

A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and in protein–protein interactions.

EPITHELIAL–MESENCHYMAL TRANSITIONS

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

ADHERENS JUNCTION

A cell–cell junction also known as zonula adherens, which is characterized by the intracellular insertion of microfilaments. If intermediate filaments are inserted in lieu of microfilaments, the resulting junction is referred to as a desmosome.

TIGHT JUNCTIONS

Belt-like regions of adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane.

HIGH MOBILITY GROUP (HMG) DOMAIN

A conserved domain that is present in HMG proteins, which are non-histone proteins involved in chromatin structure and gene regulation.

MORPHOLINO

An antisense oligonucleotide that acts specifically to block the initiation of translation.

DORSAL ROOT GANGLIA

The cell bodies of neural crest-derived sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. These cell bodies are surrounded by satellite glial cells, which share much in common with the Schwann cells that ensheath peripheral axons. Very few synapses have been observed in these ganglia.

E-BOX

The conserved nucleotide sequence CANNTG that is recognized and bound by basic helix–loop–helix and other proteins.

HOMEOBOX

A sequence of about 180 base pairs that encodes a DNA-binding protein sequence known as the homeodomain. The 60-amino-acid homeodomain comprises three α-helices.

DOMINANT-NEGATIVE

A mutant molecule that interferes with and inhibits the activation of normal molecules.

BASIC HELIX–LOOP–HELIX

(bHLH). A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

SOMITES

Paired blocks of mesoderm cells along the vertebrate body axis that form during early vertebrate development and differentiate into dermal skin, bone and muscle.

RETROELEMENTS

Segments of genetic material that transpose around the genome using an RNA intermediate.

EXPRESSED SEQUENCE TAGS

(ESTs). Short (200–500 base pairs) DNA sequences that represent the sequences expressed in an organism under a given condition. They are generated from the 3′- and 5′-ends of randomly selected cDNA clones. The purpose of EST sequencing is to scan for all the protein-coding genes, and to provide a tag for each gene on the genome.

ELECTROPORATION

The transient generation of pores in a cell membrane by exposing the cell to a high field strength electrical pulse. This allows the entry of large molecules, such as DNA constructs, into the cell.

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Gammill, L., Bronner-Fraser, M. Neural crest specification: migrating into genomics. Nat Rev Neurosci 4, 795–805 (2003). https://doi.org/10.1038/nrn1219

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