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WIREs Dev Biol
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Neural crest migration: interplay between chemorepellents, chemoattractants, contact inhibition, epithelial–mesenchymal transition, and collective cell migration

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Abstract Neural crest (NC) cells are induced at the border of the neural plate and subsequently leave the neuroepithelium during a delamination phase. This delamination involves either a complete or partial epithelium‐to‐mesenchyme transition, which is directly followed by an extensive cell migration. During migration, NC cells are exposed to a wide variety of signals controlling their polarity and directionality, allowing them to colonize specific areas or preventing them from invading forbidden zones. For instance, NC cells are restricted to very precise pathways by the presence of inhibitory signals at the borders of each route, such as Semaphorins, Ephrins, and Slit/Robo. Although specific NC chemoattractants have been recently identified, there is evidence that repulsive interactions between the cells, in a process called contact inhibition of locomotion, is one of the major driving forces behind directional migration. Interestingly, in cellular and molecular terms, the invasive behavior of NC is similar to the invasion of cancer cells during metastasis. NC cells eventually settle in various places and make an immense contribution to the vertebrate body. They form the major constituents of the skull, the peripheral nervous system, and the pigment cells among others, which show the remarkable diversity and importance of this embryonic‐stem cell like cell population. Consequently, several birth defects and craniofacial disorders, such as Treacher Collins syndrome, are due to improper NC cell migration. WIREs Dev Biol 2012, 1:435–445. doi: 10.1002/wdev.28 This article is categorized under: Early Embryonic Development > Development to the Basic Body Plan

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Pathways of neural crest (NC) cell migration. (a) Overview of the NC cell migration. The cephalic NC cells split into discrete streams, migrating around the eye and the otic vesicle. They further migrate to colonize the ventral portion of the face, the branchial arches, the heart, and the gut. At trunk levels, NC cells migrate away from the neural tube toward the skin, the anlagen of the dorsal root and sympathetic ganglia (DRG/SG), the gut, and the adrenal gland. (b) Transversal view of trunk NC cell migration. NC cells migrate dorsolaterally in between the somites and the ectoderm and ventromedially in between the neural tube and the somites. In mouse and chick, trunk NC cells pass through the rostral part of the sclerotome upon somite maturation, whereas in fish and frogs NC cells move along the medial and caudal part of the somite.

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Signal integration: how external cues and cell–cell interactions cooperate to guide neural crest (NC) cells. (a) NC cells are surrounded by inhibitory signals (brown) and exposed to positive/permissive regulators (blue). They are polarized according to their cell–cell contacts (front/rac1 activity, green; back/rhoA activity, red) where contact inhibition of locomotion (CIL, red square bracket) is taking place. At early stages of NC cell migration, cells at the front of the population experience CIL at the back and a free edge at the front and polarized along this cell contact‐free edge axis. When moving forward they create a space allowing the following cells to polarize. Polarized cells are fully responsive to external signals and migrate accordingly. (b) CIL and external inhibitors induce the collapse of cell protrusions. Downstream effectors are mainly unknown but are likely to induce an increase of rhoA activity. Conversely, positive regulators promote formation and stability of cell protrusions probably through a modulation of rac1 activity.

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Positive and negative regulators of neural crest (NC) cell migration. (a) Cephalic NC cells express a broad range of cell surface receptors and are exposed to several positive and negative guidance cues. (b) Main positive and negative signals controlling trunk NC cell migration. On one hand, inhibitory signals including class3‐semaphorins and ephrins/Eph are responsible for the formation of NC‐free spaces in between the streams. Eph and ephrins play a dual role as interaction with ephrin/Eph positive tissues can have a permissive or inhibitory outcome depending on the type of ephrins and Ephs present. On the other hand, positive signals such as sdf1, vegfa, fgf2/8, pdgfs, and class6‐semaphorins are attracting cephalic NC cells to specific locations or create permissive environments for migration.

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