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WIREs Dev Biol
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Neural crest specification: tissues, signals, and transcription factors

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Abstract The neural crest is a transient population of multipotent and migratory cells unique to vertebrate embryos. Initially derived from the borders of the neural plate, these cells undergo an epithelial to mesenchymal transition to leave the central nervous system, migrate extensively in the periphery, and differentiate into numerous diverse derivatives. These include but are not limited to craniofacial cartilage, pigment cells, and peripheral neurons and glia. Attractive for their similarities to stem cells and metastatic cancer cells, neural crest cells are a popular model system for studying cell/tissue interactions and signaling factors that influence cell fate decisions and lineage transitions. In this review, we discuss the mechanisms required for neural crest formation in various vertebrate species, focusing on the importance of signaling factors from adjacent tissues and conserved gene regulatory interactions, which are required for induction and specification of the ectodermal tissue that will become neural crest. WIREs Dev Biol 2012, 1:52–68. doi: 10.1002/wdev.8 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Signaling Pathways > Cell Fate Signaling Early Embryonic Development > Development to the Basic Body Plan

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The cellular movements during gastrulation create the necessary germ layers required for neural crest (NC) induction. NC cell gene expression begins in the ectoderm at the end of gastrulation. In chick (a), neural plate border (NPB) markers (green) are expressed surrounding the neural plate (light blue) and the primitive streak. As frog gastrulation begins (b), and during zebrafish epiboly (c), the mesoderm involutes underneath the developing epidermis. These cell movements are required to create the tissues that secrete important factors [bone morphogenetic protein (BMP), fibroblast growth factor (FGF), Wnt] required for presumptive NC cell induction (green). Diagrams are transverse section of gastrulating chick and sagittal view of gastrulating frog and zebrafish (left side) and whole embryos with anterior to the top/left and posterior to the bottom/right (right side). Blue is ectoderm, red is mesoderm, yellow is endoderm, and green is presumptive neural crest.

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The future premigratory neural crest gene regulatory network (NC GRN). The ‘transcriptional state’ of NC at any given time can be defined as the sum of interactions between transcription factors and modulation of their activity by neural crest (NC) modifiers (molecules involved in chromatin remodeling, post‐transcriptional/ translational modification, and other signaling pathways). NC modifiers that act upstream and downstream of NC specifiers (blue arrows) modify the ‘transcriptional state’ of the NC (green arrow), thereby affecting progenitor maintenance, survival, and EMT. By altering the ‘transcriptional state’, various NC subpopulations can be generated (e.g., trunk vs cranial NC).

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The pan‐vertebrate premigratory cranial neural crest gene regulatory network (CNC GRN) model. Generated using Bio Tapestry software93 and compiled from gene perturbation studies from multiple species.4 The GRN shows subnetworks of transcription factors during neural plate (NP) border specification (gray) and premigratory neural crest (NC) specification (white). AP2 is represented twice in the network based on recent evidence that it acts as both an NP border specifier and as an NC specifier.94 Solid lines: direct regulatory interactions based on promoter and cis‐regulatory analysis. Dashed lines: potential direct interactions. Broken lines: potential interactions. Bubble nodes: protein–protein interactions.

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Signaling pathways involved in neural crest induction. From left to right: Bone morphogenetic protein (BMP) activates Smad 1,5,8 proteins that interact with co‐Smad to activate transcription of neural plate border (NPB) (Msx1,2) and neural crest (NC) specifier (Snail2) genes. Retinoic acid (RA) functions as a transcriptional regulator to posteriorize neural tissues, and inhibits BMP signaling and expression of FGF8 and Wnt8. Fibroblast growth factor (FGF) signals through one of its three downstream pathways (Akt, PLCγ, Ras/Erk) to activate expression of Wnt or to inhibit BMP expression indirectly regulating NC development. Notch/Delta interaction activates the Notch intracellular domain (NICD) which then binds to CSL transcription factors to activate expression of the NPB gene Hairy2 (frog) or activates expression of BMP, indirectly inducing NC (chick). Wnt binds to the frizzled and LRP5/6 receptors which allows for the accumulation of β‐catenin in the cell. β‐catenin binds to the Wnt effector TCF/LEF to activate NPB gene Pax3/7, which activates neural crest genes. Gray arrows indicate the consistent requirement for these signaling pathways throughout neural crest development.

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Morphogen expression patterns. (a) In the chicken embryo, BMP4 is expressed in the ectoderm and neural plate border (NPB), FGF8, and Notch1 are expressed in the mesoderm, and Wnt8 is expressed in the NPB and the mesoderm. (b) In the Xenopus embryo, BMP4 is expressed in the developing epidermis and mesoderm and FGF8, Notch1, and Wnt8 are expressed in the mesoderm. Wnt8 is also expressed in the NPB and Notch1 is expressed in the neural plate. (c) In Zebrafish embryos, BMP2b is expressed in the developing epidermis and mesoderm. FGF8a, Wnt8, and Notch1 are expressed in the involuting mesoderm and Notch1 is also expressed in the neural plate. (d) In situ hybridization of BMP4 in a chick embryo showing that BMP4 is highly expressed in the presumptive neural crest region at levels of different rostrocaudal fates (Reprinted with permission from Ref 2. Copyright 2009 Elsevier) The differences in expression of these morphogens may explain some of the differences in neural crest (NC) induction between organisms. Embryos are depicted as follows: (a,c) Anterior to the top, posterior to the bottom, dorsal up. (b) Anterior to the top, posterior to the bottom, and dorsal to right. All expression patterns (a–c) were found in Xenbase, ZFIN, and Geisha.

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Neurulation and neural crest induction. (a) Secreted factors from the surrounding tissues [bone morphogenetic protein (BMP), fibroblast growth factor (FGF), Wnt] pattern the presumptive neural crest region or NPB. (b) As the neural tube closes, neural crest specification is complete and they begin to express neural crest specifier genes such as Foxd3, Slug, and Sox10.

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Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
Early Embryonic Development > Development to the Basic Body Plan