Collective Cell Migration in Neural Crest Development


The migration of multiple cells as a cooperative unit known as collective cell migration is a common phenomenon in development, cancer and healing. Cooperation can be implemented by physical and/or chemical means and thus happens in epithelial as well as mesenchymal cell populations. Neural crest cells, a highly motile embryonic population, are a well‐known model for epithelial–mesenchymal transition and cell migration. Neural crest cells use various strategies to cooperate and migrate collectively which make them a good model for the study of collectiveness. Further, neural crest cells' interaction with other embryonic populations also relies on cell cooperation, thus providing a model for the study of cell cooperation during organogenesis.

Key Concepts

  • Neural crest cells are migratory multipotent stem cells.
  • Neural crest cells distribute according to cell–cell and cell–environment interactions.
  • Some neural crest cell populations migrate collectively.
  • Collectiveness is based on cell–cell cooperation via paracrine chemotaxis and cell–cell adhesion.
  • Collectiveness influences cell guidance.
  • Cooperation takes place at several orders of magnitude: among neural crest cells and between neural crest cells and adjacent cell populations.

Keywords: collective migration; epithelial–mesenchymal transition; neural crest; directional migration; development; cell adhesion; cadherins; polarity; chemotaxis

Figure 1. Overview of neural crest development. (a) Dorsal view of a vertebrate embryo at early neurula stage, neural crest (NC) cells are lateral to the neural plate (NP). (b) Dorsal view of a vertebrate embryo at late neurula stage, NC cells are located along the midline. (c–e) Transversal sections showing the relative positions of the ectoderm, NC, NP and mesoderm at early neural stage (c), late neurula stage (d) and after neural crest emigration (e). (f–h) Dorsal views depicting the antero‐posterior wave of neural crest emigration. Note that neural crest cells rapidly organise in discrete streams around obstacles of chemical nature (i.e. mesenchyme adjacent to rhombomere 3 (r3) which is rich in semaphorin) or physical nature (i.e. the otic vesicle and the eyes). (i) Detail of the migration of the ventro‐medial trunk neural crest cells in between epithelial somites, through the sclerotome and aggregating to form ganglia of the peripheral nervous system. Anlagen of ganglia are marked by dotted circles. DRG, dorsal root ganglion; SG, sympathetic ganglion.
Figure 3. Neural emigration and dispersion. (a) Overview of the main driving forces of neural crest dissemination. Neural crest cells (blue) emerge from the dorsal neuroepithelium (blue) as a continuous wave of single cells at high cell density. They disperse through the extracellular space. During migration, they encounter various constraints in the environment that force them into organising in specific streams. In addition, positive signals may drive some neural crest subpopulations into specific niche. (b) Transversal section through the dorsal neural tube at the time of neural crest delamination. The process of EMT can be summarised in three main steps: loss of apical cell–cell junction, apical retraction and protrusion into the extracellular space. These steps need not happen in that order. This is followed by migration away from the neural tube. During this process, there is a quantitative and qualitative change of cadherin expression as well as dynamic regulation of Rho and Rac activities. (c) During migration, neural crest cells experience contact inhibition of locomotion (CIL) which controls cell polarity in a cell–cell contact‐dependent manner. The main steps of CIL are depicted here: cells colliding, formation of a transient contact involving cadherins N and 11, activation of Wnt/PCP and RhoA and repolarisation and migration in opposite direction.
Figure 2. Mechanisms of cell cooperation leading to collectiveness. (a) Diagram of a stream of migrating neural crest cells. Cells on the outskirts of the group may leave owing to contact inhibition of locomotion but eventually come back due to co‐attraction, see the main text for details. (b) Pseudo‐kymograph representing the dynamics of membranes of two adjacent cells within the group. Note that cells keep being attracted to one another by co‐attraction (C3a/C3aR pathway) and repelled upon contact via contact inhibition of locomotion (N‐cadherin‐Wnt/PCP‐RhoA‐ROCK pathway). These attraction–repulsion cycles maintain the migratory population dense but nonetheless fluid. (c) In cells located at the leading edge of the population, co‐attraction and contact inhibition set the polarity of small GTPases RhoA and Rac1 which is further modulated by chemotaxis downstream of Sdf1/Cxcr4. (d) In cells that are isolated from the group, there is no long‐lasting polarity due to the absence of repeated feedback from co‐attraction and contact inhibition. As such the effect of Sdf1 signalling on polarity is reduced. Consequently, migratory neural crest cells that do not travel at high cell density poorly chemotax.
Figure 4. Collective migration in cell populations interacting with neural crest cells. (a) Dorsal view of a Xenopus gastrula. Mesodermal cells invaginate underneath the ectoderm and the prospective neural plate and neural crest. (b) Sagittal section of a Xenopus gastrula. (c) Inset showing the collective migration of mesodermal cells underneath the neural plate/crest territory. Cells are polarised due to intercellular tensions mediated by C‐cadherin junctions building up from the leading edge down. (d) Lateral views of Xenopus embryos at late neurula stage showing the coordinated dorso‐ventral migration of neural crest cells expressing Cxcr4 and placodal cells expressing Sdf1. (e) Details of the neural crest–placode interaction. Neural crest cells are attracted to Sdf1 produced by the placodes. Upon physical contact, both cell types undergo contact inhibition of locomotion and retract their protrusions. Neural crest cells, being more migratory, fill the gap first. The cycle of attraction–repulsion repeats itself. The higher motility of neural crest cells creates a bias and generates directional movement of placodal cells away from neural crest cells. That displaces the source of Sdf1 and promotes further migration of the neural crest cells.


Alfandari D, Cousin H, Gaultier A, et al. (2001) Xenopus ADAM 13 is a metalloprotease required for cranial neural crest‐cell migration. Current Biology 11: 918–930.

Banerjee S, Gordon L, Donn TM, et al. (2011) A novel role for MuSK and non‐canonical Wnt signaling during segmental neural crest cell migration. Development 138: 3287–3296.

Barriga EH, Maxwell PH, Reyes AE and Mayor R (2013) The hypoxia factor Hif‐1alpha controls neural crest chemotaxis and epithelial to mesenchymal transition. The Journal of Cell Biology 201: 759–776.

Becker SF, Mayor R and Kashef J (2013) Cadherin‐11 mediates contact inhibition of locomotion during Xenopus neural crest cell migration. PloS One 8 e85717.

Cai D, Chen SC, Prasad M, et al. (2014) Mechanical feedback through E‐cadherin promotes direction sensing during collective cell migration. Cell 157: 1146–1159.

Carmona‐Fontaine C, Matthews HK, Kuriyama S, et al. (2008) Contact inhibition of locomotion in vivo controls neural crest directional migration. Nature 456: 957–961.

Carmona‐Fontaine C, Theveneau E, Tzekou A, et al. (2011) Complement fragment C3a controls mutual cell attraction during collective cell migration. Developmental Cell 21: 1026–1037.

Chalpe AJ, Prasad M, Henke AJ and Paulson AF (2010) Regulation of cadherin expression in the chicken neural crest by the Wnt/beta‐catenin signaling pathway. Cell Adhesion & Migration 4: 431–438.

Cheung M and Briscoe J (2003) Neural crest development is regulated by the transcription factor Sox9. Development 130: 5681–5693.

Cheung M, Chaboissier MC, Mynett A, et al. (2005) The transcriptional control of trunk neural crest induction, survival, and delamination. Developmental Cell 8: 179–192.

Christian L, Bahudhanapati H and Wei S (2013) Extracellular metalloproteinases in neural crest development and craniofacial morphogenesis. Critical Reviews in Biochemistry and Molecular Biology 48: 544–560.

Clay MR and Halloran MC (2014) Cadherin 6 promotes neural crest cell detachment via F‐actin regulation and influences active Rho distribution during epithelial‐to‐mesenchymal transition. Development 141: 2506–2515.

Cousin H, Abbruzzese G, Kerdavid E, Gaultier A and Alfandari D (2011) Translocation of the cytoplasmic domain of ADAM13 to the nucleus is essential for Calpain8‐a expression and cranial neural crest cell migration. Developmental Cell 20: 256–263.

Creuzet S, Couly G, Vincent C and Le Douarin NM (2002) Negative effect of Hox gene expression on the development of the neural crest‐derived facial skeleton. Development 129: 4301–4313.

Culbertson MD, Lewis ZR and Nechiporuk AV (2011) Chondrogenic and gliogenic subpopulations of neural crest play distinct roles during the assembly of epibranchial ganglia. PloS One 6 e24443.

Dumortier JG, Martin S, Meyer D, Rosa FM and David NB (2012) Collective mesendoderm migration relies on an intrinsic directionality signal transmitted through cell contacts. Proceedings of the National Academy of Sciences of the United States of America 109: 16945–16950.

Erickson CA (1985) Control of neural crest cell dispersion in the trunk of the avian embryo. Developmental Biology 111: 138–157.

Etienne‐Manneville S (2014) Neighborly relations during collective migration. Current Opinion in Cell Biology 30: 51–59.

Fairchild CL, Conway JP, Schiffmacher AT, Taneyhill LA and Gammill LS (2014) FoxD3 regulates cranial neural crest EMT via downregulation of tetraspanin18 independent of its functions during neural crest formation. Mechanisms of Development 132: 1–12.

Friedl P, Wolf K and Zegers MM (2014) Rho‐directed forces in collective migration. Nature Cell Biology 16: 208–210.

Fukui A, Goto T, Kitamoto J, Homma M and Asashima M (2007) SDF‐1 alpha regulates mesendodermal cell migration during frog gastrulation. Biochemical and Biophysical Research Communications 354: 472–477.

Kashef J, Kohler A, Kuriyama S, et al. (2009) Cadherin‐11 regulates protrusive activity in Xenopus cranial neural crest cells upstream of Trio and the small GTPases. Genes & Development 23: 1393–1398.

Kirby ML and Hutson MR (2010) Factors controlling cardiac neural crest cell migration. Cell Adhesion & Migration 4: 609–621.

Kulesa PM and Gammill LS (2010) Neural crest migration: patterns, phases and signals. Developmental Biology 344: 566–568.

Kuriyama S, Theveneau E, Benedetto A, et al. (2014) In vivo collective cell migration requires an LPAR2‐dependent increase in tissue fluidity. The Journal of Cell Biology 206: 113–127.

Mayor R and Carmona‐Fontaine C (2010) Keeping in touch with contact inhibition of locomotion. Trends in Cell Biology 20: 319–328.

Mayor R and Theveneau E (2013) The neural crest. Development 140: 2247–2251.

McCusker C, Cousin H, Neuner R and Alfandari D (2009) Extracellular cleavage of cadherin‐11 by ADAM metalloproteases is essential for Xenopus cranial neural crest cell migration. Molecular Biology of the Cell 20: 78–89.

McLennan R, Teddy JM, Kasemeier‐Kulesa JC, Romine MH and Kulesa PM (2010) Vascular endothelial growth factor (VEGF) regulates cranial neural crest migration in vivo. Developmental Biology 339: 114–125.

Monier‐Gavelle F and Duband JL (1997) Cross talk between adhesion molecules: control of N‐cadherin activity by intracellular signals elicited by beta1 and beta3 integrins in migrating neural crest cells. The Journal of Cell Biology 137: 1663–1681.

Moore R, Theveneau E, Pozzi S, et al. (2013) Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion. Development 140: 4763–4775.

Nakagawa S and Takeichi M (1998) Neural crest emigration from the neural tube depends on regulated cadherin expression. Development 125: 2963–2971.

Nitzan E, Krispin S, Pfaltzgraff ER, et al. (2013) A dynamic code of dorsal neural tube genes regulates the segregation between neurogenic and melanogenic neural crest cells. Development 140: 2269–2279.

Park KS and Gumbiner BM (2012) Cadherin‐6B stimulates an epithelial mesenchymal transition and the delamination of cells from the neural ectoderm via LIMK/cofilin mediated non‐canonical BMP receptor signaling. Developmental Biology 366: 232–243.

Piloto S and Schilling TF (2010) Ovo1 links Wnt signaling with N‐cadherin localization during neural crest migration. Development 137: 1981–1990.

Powell DR, Blasky AJ, Britt SG and Artinger KB (2013) Riding the crest of the wave: parallels between the neural crest and cancer in epithelial‐to‐mesenchymal transition and migration. Wiley Interdisciplinary Reviews. Systems Biology and Medicine 5: 511–522.

Pryor SE, Massa V, Savery D, et al. (2014) Vangl‐dependent planar cell polarity signalling is not required for neural crest migration in mammals. Development 141: 3153–3158.

Rios AC, Serralbo O, Salgado D and Marcelle C (2011) Neural crest regulates myogenesis through the transient activation of NOTCH. Nature 473: 532–535.

Rovasio RA, Delouvee A, Yamada KM, Timpl R and Thiery JP (1983) Neural crest cell migration: requirements for exogenous fibronectin and high cell density. The Journal of Cell Biology 96: 462–473.

Sasselli V, Pachnis V and Burns AJ (2012) The enteric nervous system. Developmental Biology 366: 64–73.

Sauka‐Spengler T and Bronner M (2010) Snapshot: neural crest. Cell 143 (486–486): e481.

Schiffmacher AT, Padmanabhan R, Jhingory S and Taneyhill LA (2014) Cadherin‐6B is proteolytically processed during epithelial‐to‐mesenchymal transitions of the cranial neural crest. Molecular Biology of the Cell 25: 41–54.

Shoval I, Ludwig A and Kalcheim C (2007) Antagonistic roles of full‐length N‐cadherin and its soluble BMP cleavage product in neural crest delamination. Development 134: 491–501.

Strobl‐Mazzulla PH and Bronner ME (2012a) Epithelial to mesenchymal transition: new and old insights from the classical neural crest model. Seminars in Cancer Biology 22: 411–416.

Strobl‐Mazzulla PH and Bronner ME (2012b) A PHD12‐Snail2 repressive complex epigenetically mediates neural crest epithelial‐to‐mesenchymal transition. The Journal of Cell Biology 198: 999–1010.

Stuhlmiller TJ and Garcia‐Castro MI (2012) Current perspectives of the signaling pathways directing neural crest induction. Cellular and Molecular Life Sciences 69: 3715–3737.

Taneyhill LA, Coles EG and Bronner‐Fraser M (2007) Snail2 directly represses cadherin6B during epithelial‐to‐mesenchymal transitions of the neural crest. Development 134: 1481–1490.

Taneyhill LA and Schiffmacher AT (2013) Cadherin dynamics during neural crest cell ontogeny. Progress in Molecular Biology and Translational Science 116: 291–315.

Teddy JM and Kulesa PM (2004) In vivo evidence for short‐ and long‐range cell communication in cranial neural crest cells. Development 131: 6141–6151.

Theveneau E, Duband JL and Altabef M (2007) Ets‐1 confers cranial features on neural crest delamination. PloS One 2: e1142.

Theveneau E, Marchant L, Kuriyama S, et al. (2010) Collective chemotaxis requires contact‐dependent cell polarity. Developmental Cell 19: 39–53.

Theveneau E and Mayor R (2011) Can mesenchymal cells undergo collective cell migration? The case of the neural crest. Cell Adhesion & Migration 5: 490–498.

Theveneau E and Mayor R (2012a) Cadherins in collective cell migration of mesenchymal cells. Current Opinion in Cell Biology 24: 677–684.

Theveneau E and Mayor R (2012b) Neural crest delamination and migration: from epithelium‐to‐mesenchyme transition to collective cell migration. Developmental Biology 366: 34–54.

Theveneau E, Steventon B, Scarpa E, et al. (2013) Chase‐and‐run between adjacent cell populations promotes directional collective migration. Nature Cell Biology 15: 763–772.

Trepat X and Fredberg JJ (2011) Plithotaxis and emergent dynamics in collective cellular migration. Trends in Cell Biology 21: 638–646.

Weber GF, Bjerke MA and DeSimone DW (2012) A mechanoresponsive cadherin‐keratin complex directs polarized protrusive behavior and collective cell migration. Developmental Cell 22: 104–115.

Wysoczynski M, Kucia M, Ratajczak J and Ratajczak MZ (2007) Cleavage fragments of the third complement component (C3) enhance stromal derived factor‐1 (SDF‐1)‐mediated platelet production during reactive postbleeding thrombocytosis. Leukemia 21: 973–982.

Xu X, Li WE, Huang GY, et al. (2001) Modulation of mouse neural crest cell motility by N‐cadherin and connexin 43 gap junctions. The Journal of Cell Biology 154: 217–230.

Further Reading

Developmental Biology, Special Issue on Neural Crest (2012).

Hall BK and Hall BK (2009) The Neural Crest and Neural Crest Cells in Vertebrate Development and Evolution, 2nd edn. New York: Springer.

Trainor PA (2014) Neural Crest Cells: Evolution, Development and Disease. Amsterdam: Elsevier/AP.

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Theveneau, Eric, and Andrieu, Cyril(Jun 2015) Collective Cell Migration in Neural Crest Development. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025976]