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The neural crest, a cell type found only in vertebrate embryos, gives rise to the structures of the skull and face and most of the peripheral nervous system, as well as other cell types characteristic of vertebrates. These cells are of great clinical significance and a wide variety of congenital defects are due to aberrant neural crest development. Increasing numbers of studies are contributing to our understanding of how this group of cells form and differentiate during normal development. Wnt, FGF, BMP, and Notch-mediated signals all have essential roles in this process, and several of these signals appear to play multiple temporally distinct roles. Changes in the response of neural crest cells to the same signal over time may be mediated, in part, by an ever-changing cocktail of transcription factors expressed within these cells. Neural crest development is thus a complex multistep process, and elucidating the molecular mechanisms that mediate distinct aspects of this process will require that we determine the role of each of these factors alone and in combination. Here, we review some recent advances in our understanding of the signals and downstream transcription factors involved in neural crest cell formation.
Figure 1. A: Schematic summarizing the combinatorial signals implicated in neural crest induction. A gradient of BMP signaling is believed to pattern the early ectoderm, with high levels of BMP signaling specifying epidermal fates. The neural plate forms in regions of low or absent BMP signaling, while intermediate levels of BMP signaling are permissive for neural crest induction. A Wnt signal (red arrows) originating from either the prospective epidermis or the paraxial mesoderm is required for neural crest formation. FGF signals (black arrows) and Notch signals (yellow arrows) have also been implicated in this process. B: During neurulation, the neural plate will form the neural tube, with neural crest precursors localized dorsally. Following neural tube closure, neural crest cells undergo an epithelial-to-mesenchymal transition (EMT) and migrate extensively to target sites where they will give rise to a diversity of cell types. BMP, Wnt, and Notch signals are also implicated in these later stages of neural crest development.
Figure 2. The transcriptional response to the combined signals that pattern the early ectoderm is complex, as illustrated by the expression at neural plate stages of six transcription factors implicated in neural crest formation in Xenopus. A:AP2-α is expressed in the prospective epidermis (yellow asterisk), but not in the neural crest at neural plate stages. Later, however, it will be expressed in neural crest precursors in craniates. B:Pax3 is expressed in two broad regions that include placode, neural crest, and dorsal CNS precursors. Msx-1 has a highly similar expression pattern at these stages. C:Hairy2a, a proposed transcriptional readout for Notch signals, is most strongly expressed at the neural plate border and in the floor plate (green asterisk), although there is also low-level expression in the neural plate. D:c-myc is expressed in both the neural crest and placode precursors at the neural plate border, as well as in the transverse neural fold that will give rise to forebrain and the retinal and olfactory primordia. E: Similar to c-myc, Opl expression marks the lateral and transverse neural folds, but unlike c-myc, Opl is also expressed in the developing ear.F: The expression of Slug specifically marks the prospective neural crest (red asterisk).
Figure 3. Phylogenetic origins of the neural crest. A: Cladogram illustrating the evolutionary significance of the neural crest with respect to extant organisms and groups. Though some genes used as “markers” for neural crest are expressed in suggestively similar patterns in the Urochordata (tunicates) and the Cephalochordata (amphioxus), definitive neural crest is restricted to the Craniata, and is considered a defining characteristic of the group. The term “Craniata” is often used interchangeably with “vertebrates,” though technically it also includes the Myxini (hagfish). Understanding the evolutionary transition to neural crest requires studies of the extant groups that arose proximal to this transition, including nonvertebrate chordates and the most basal extant vertebrates, Petromyzontiformes (lampreys). B: Expression of Snail and AP2 orthologs in Amphioxus embryos at neural plate stages. Snail is expressed at the neural plate border, as in craniates. Similarly, AP2 is found in the ectoderm at neural plate stages. In contrast to craniates, however, expression of Amphi-AP2 never colocalizes with Snail at the neural plate border. Photos of Amphioxus in situs courtesy of D. Meulmans.
