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Specifying neural crest cells: From chromatin to morphogens and factors in between

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Neural crest (NC) cells are a stem‐like multipotent population of progenitor cells that are present in vertebrate embryos, traveling to various regions in the developing organism. Known as the “fourth germ layer,” these cells originate in the ectoderm between the neural plate (NP), which will become the brain and spinal cord, and nonneural tissues that will become the skin and the sensory organs. NC cells can differentiate into more than 30 different derivatives in response to the appropriate signals including, but not limited to, craniofacial bone and cartilage, sensory nerves and ganglia, pigment cells, and connective tissue. The molecular and cellular mechanisms that control the induction and specification of NC cells include epigenetic control, multiple interactive and redundant transcriptional pathways, secreted signaling molecules, and adhesion molecules. NC cells are important not only because they transform into a wide variety of tissue types, but also because their ability to detach from their epithelial neighbors and migrate throughout developing embryos utilizes mechanisms similar to those used by metastatic cancer cells. In this review, we discuss the mechanisms required for the induction and specification of NC cells in various vertebrate species, focusing on the roles of early morphogenesis, cell adhesion, signaling from adjacent tissues, and the massive transcriptional network that controls the formation of these amazing cells. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Signaling Pathways > Cell Fate Signaling
Morphogenesis and NC specification. (a, a′) In chicken embryos, the NPB (green) is specified by Hamburger Hamilton stage 5 (HH5) prior to the onset of definitive neural crest (NC) markers and expresses transcription factors such as MSX1, ZIC1, and PAX7. (b, b′) As neurulation proceeds at HH7‐HH8, the neural folds rise and bend toward the midline. At this stage the neural folds are being specified as definitive NC cells. (c, c′) By HH8, definitive NC markers are expressed in the dorsal neural tube (SOX9, SOX10, SNAI2, and FOXD3), the neural tube is closed, and the ectodermal cells are converging on the midline to cover the neural tube. (d, d′) By HH9, the NC cells are beginning to undergo EMT and start detaching from the neural tube. ECT, ectoderm; NC, neural crest; NF, neural folds; NPB, neural plate border; NP, neural plate
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The NC gene regulatory network (GRN) is constantly evolving. This GRN was compiled from gene perturbation studies from multiple species including chick, frog, mouse and zebrafish. The GRN displays the regulatory interactions between signaling factors (top level) and their intracellular effectors and downstream transcriptional targets. The NP (left) and epidermis (right) are depicted on either side of the NC as they would be in a developing embryo. NPB specification (green), premigratory NC specification (blue), and NC EMT factors (yellow) are shown. Pax3/7, Tfap2 are both represented twice because they have been identified as both border specifiers and NC specifiers. Solid lines indicate direct regulatory interactions based on promoter and cis‐regulatory analysis. Verified animal models are marked next to each direct interaction (c, chick; m, mouse; x, frog, f, fish). Signaling factors are represented as proteins in all capitals while GRN transcription factors are lower case and capitalized, but not italicized, to demonstrate that they represent both functional proteins and gene targets. Dashed lines represent functional interactions without evidence of direct interaction so far. Bubble nodes: Protein–protein interactions
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Recent technological advances have allowed more in depth study of the NC regulatory levels. Diagram shows the different intracellular control levels that regulate how and when NC cells form and the assays that can be used to perform systems analysis of NC formation. (Left) Depiction of a cell with multiple levels of genetic and proteomic regulation and where in the cell these processes take place (cytoplasm vs. nucleus). Specific types of cellular regulation are identified at three different levels: The general levels of regulation starting from extracellular morphogens that activate intercellular cascades followed by regulation of DNA transcription, mRNA availability, stability and translation, and protein stability, modification and degradation. Column 2 shows the types of analyses used to identify the changes at the previous levels. Finally, specific examples of genes, mRNAs, microRNAs and proteins that are regulated at these levels during NC development with references
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Embryonic NC cells vs. human induced NC cells (HiNCs). Schematic comparing (a) the development and isolation of embryonic NC cells versus (b) the technique used to create human induced NC cells from differentiated fibroblasts. To create human induced pluripotent NC cells, fibroblasts must first be de‐differentiated by reprogramming them using the Yamanaka stem cell factors, Oct4, Sox2, Nanog, and Klf4. Then by using the appropriate media (various), those stem cells can be differentiated into NC cells in vitro
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Comparative gene expression of morphogens and NC transcription factors in frog and chick. Diagrams depicting the expression of NC transcription factors Pax3/7 and Snai2 compared to various genes coding for morphogens that regulate their early expression (Bmp2/4, Wnt1/8A, and Fgf2/4/8). (a, b) In the frog embryo, Pax3 is expressed by late gastrula stage (stage 12.5) in the presumptive NC region adjacent to the NP. Its expression is broader than Snai2, which is also in the presumptive NC region. At this stage, Bmp4, Fgf2, and Wnt8 transcripts are expressed posteriorly near the blastopore. At neurula stage (stage 17), the NC cells are preparing to migrate ventrolaterally away from the midline, and the expression of both Pax7 and Snai2 remains adjacent to the rising neural folds. At this stage, BMPs remain in the nonneural ectoderm and mesoderm while Fgf8 is expressed in the anterior region, in the brain, and Fgf2 and Fgf4 are in the posterior mesoderm. By stage 17, Wnt8 is expressed in the developing neural folds. (c, d) At late gastrula stage (HH5) in the chicken embryo, Pax7 is expressed in the NPB, but Snai2 is limited to the primitive streak/mesoderm. Bmp4 is expressed in the ectoderm and NPB, Fgf8 is expressed in the mesoderm, and Wnt8 is expressed in the NPB and the mesoderm. At neurula stage (HH8), Pax7 is expressed in the definitive NC as well as the dorsal neural tube, and the NPB in the posterior region. Snai2 is expressed in the definitive NC cells in the head. Bmp4 is expressed in the neural folds and the mesoderm, and Wnt1 is expressed in the dorsal neural folds and Wnt8A is expressed in the paraxial mesoderm. The differences in expression of these morphogens may explain some of the differences in NC induction between organisms. Embryos are depicted as follows: (a, c) Anterior to the top, posterior to the bottom, dorsal out. (b, d) Dorsal up, ventral down. All expression patterns (a–d) were found in Xenbase and Geisha
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Developmental stages and molecules involved in NC specification and migration. Prior to differentiation, NC cells go through three stages (left column), neural plate border (NPB), premigratory NC (PNC), and migratory NC (MNC). The nonneural ectoderm (NNE) develops lateral to the NPB cells during neurulation as the neural folds (NF) rise to form the neural tube (NT). At these early stages, signaling from WNTs, FGFs, BMPs, and BMP antagonists (Noggin, Chordin) (middle column) drives the specification of the NPB specifiers (right column). As the NT closes, NC cells are specified in the dorsal NT, and are marked by NC specifier transcription factors. Along with signaling from WNTs, BMPs, RA, and FGFs, the NC specifiers down regulate adhesive cadherins, upregulate migratory cadherins and the cells leave the neural tube. The neural and nonneural ectoderm is pink and green, premigratory and migratory NC are orange
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Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms
Nervous System Development > Vertebrates: General Principles