Vertebrate Embryo: Patterning the Neural Crest Lineage

Abstract

Neural crest (NC) cells form as epithelial progenitors during the process of neurulation, then undergo an epithelio‐mesenchymal transition and become motile. As mesenchymal cells, they migrate through stereotypical pathways, reach their homing sites and differentiate into a large variety of derivatives that are specific and variable along the embryonic axis. These include neurons and glia of the sensory and autonomic nervous system, pigment cells, chromaffin cells of the adrenal gland and mesectoderm in the head region. Given that a few initial progenitors expand and diversify so substantially, the NC provides an excellent model to investigate fundamental questions in Developmental Biology, that is, defining the state of commitment of the different precursors throughout ontogeny, unravelling the nature of cellular interactions among adjacent crest cells and between crest progenitors and their environment, and elucidating the molecular basis of lineage segregation, cell migration and terminal differentiation.

Key Concepts:

  • NC progenitors are multipotent at the population level and become differentially restricted during ontogeny.

  • Lineage segregation in the trunk is likely to begin before NC emigration from the neural tube.

  • Epithelio‐mesenchymal transition of NC progenitors is orchestrated by a network of secreted factors (BMP/noggin and Wnt1) acting in concert with adhesion molecules, RhoGTPases, extracellular matrix components and cell intrinsic determinants.

  • NC cells migrate stereotypically to their homing sites and migration seems to be largely channelled by interactions between inhibitory environmental signals and NC cells expressing their cognate receptors.

  • Contact inhibition mediated by noncanonical Wnt signalling contributes to the directionality of NC migration.

  • Specification and subsequent differentiation of NC progenitors into the various phenotypes are regulated by reiterative signals (i.e. BMPs, Wnts) that induce lineage‐specific codes of transcription factors.

  • In spite of undergoing early fate restrictions in vivo, some NC cells, even following differentiation, retain significant plasticity as evidenced by in vitro analysis.

Keywords: cell migration; cell specification; enteric nervous system; epithelio‐mesenchymal conversion; melanocyte; neuron; peripheral nervous system; sensory; Schwann; sympathetic

Figure 1.

Pre‐migratory and migrating neural crest (NC) cells revealed by various markers. (a) In situ hybridisation for Slug messenger ribonucleic acid, a transcription factor expressed in the tips of the closing neural folds (arrowheads) that is likely to mark at least a subset of early pre‐migratory NC cells. (b) The neural primordium (neural tube containing pre‐migratory NC) was transplanted from a quail donor into an equivalent chick host and incubated until the time of NC migration. The micrograph illustrates NC cells expressing the quail marker (condensed nucleolar heterochromatin; arrowheads) migrating through the intersomitic space composed of chick cells (dispersed heterochromatin; light nuclear staining). (c, d) NC cells stained with the HNK‐1 monoclonal antibody (brown colour) at the beginning of migration opposite the somite (c) and at an early post‐migratory stage (d) showing the localisation of immunolabelled cells to the primordia of the dorsal root ganglion (DRG), sympathetic ganglion (SG) and ventral root (VR), where NC cells develop into Schwann cells that line the peripheral nerves.

Figure 2.

Segmental migration of neural crest (NC) cells in the trunk depends upon intrinsic differences between rostral and caudal somitic domains. (a, b) Frontal sections of a 3‐day‐old chick embryo through the level of the DRG (a) and ventral roots (b) to illustrate the presence of segmentally organised sensory ganglia and nerves (Schwann cell precursors) stained with the HNK‐1 antibody. Note that ganglia and nerves form within the rostral domain of each somite exclusively. (c–e) Three‐dimensional reconstructions of (c) the normal side of an embryo showing normal segmentation of DRG (yellow), ventral roots (green) and sympathetic ganglia (purple). In (d), the operated side of an embryo in which normal somites were replaced by multiple rostral‐half somites before NC emigration, note the total loss of segmentation of peripheral ganglia and nerves, which are now continuous along the grafted area. (e) The operated side of an embryo that received multiple caudal‐half somites in the place of the normal mesoderm. Note the absence of peripheral neural derivatives along the grafted area. Instead, both NC cells and peripheral nerves circumvent the caudal mesodermal graft and localise to its edges. NT, neural tube; S, somite. In all panels, rostral is to the right.

Figure 3.

Early fate restriction of neural progenitors of the NC. (a) and (a′) illustrate the early and late phases of NC migration, respectively. The early phase is characterised by ventral streams of migrating progenitors that yield sensory and sympathetic ganglia and Schwann cells (neural progenitors are coloured red). The late phase is characterised by a dorsolateral migration of progenitors under the ectoderm that generate melanocytes (coloured yellow). (b) Missexpression of DNA encoding the endothelin receptor type B2 (EdnRB2) into neural progenitors diverts their migration towards the dorsolateral pathway, yet they upregulate neural traits even in ectopic locations. (c) When young neural tubes are grafted into a mature host environment conducive to melanogenesis, neural progenitors still migrate ventrally and incorporate into host DRG (not shown and see Krispin et al., ). (d) If transfected with EdnRB2 before grafting, NC cells are diverted into the dorsolateral pathway where they nevertheless upregulate neural markers. DM, dermomyotome; Ect, ectoderm; M, myotome; NT, neural tube.

Figure 4.

Two populations of NC‐derived melanocytes. (I) Melanocytes generated from a late emigrating‐early differentiating subset of NC progenitors; these delaminate directly from the NT (arrows), are dorsally located and migrate along the subectodermal pathway to invade the epidermis. (II) A second population derives from Schwann cell progenitors of the spinal nerves (arrows) that comprise an early migrating NC subset. Their differentiation is late when compared to the dorsal melanocytes. Melanocytes are coloured yellow and neural derivatives are in red. DRG, dorsal root ganglion; M, myotome; NO, notochord; NT, neural tube; SG, sympathetic ganglia; SN, spinal nerve.

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Nitzan, Erez, and Kalcheim, Chaya(Oct 2011) Vertebrate Embryo: Patterning the Neural Crest Lineage. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000738.pub3]