Redistribution of Adhesive Forces through Src/FAK Drives Contact Inhibition of Locomotion in Neural Crest

Roycroft, Alice; Szabó, András; Bahm, Isabel; Daly, Liam; Charras, Guillaume; Parsons, Maddy; Mayor, Roberto

doi:10.1016/j.devcel.2018.05.003

Cited by 38 publications

(42 citation statements)

References 91 publications

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“…We previously showed that EphB2 activation of Sox2 results in the clustering of SCs but video analysis showed these clustered cells appeared to maintain CIL, as the cells appeared to be attempting to migrate away from the cluster 12 . This is consistent with the migration of SC cords during nerve regeneration, which would be predicted to require a force such as CIL to drive migration forward 18,21,23,24 . N-cadherin has been implicated in CIL in other cell types 21,22,25 , so we addressed whether N-cadherin was also required for the regulation of collective SC migration.…”

Section: N-cadherin Is Required For Contact Inhibition Of Locomotion supporting

confidence: 77%

“…CIL can provide an outward force in collectively migrating cells [21][22][23] . To test if the Slit CIL signal is important for the collective migration of SCs, we performed a wound-healing assay with SCs knocked down for Slit2 and Slit3 and found that this was sufficient to decrease the collective migration of these cells ( Fig.…”

Section: Slit Is Required For the Efficient Collective Migration Of Smentioning

confidence: 99%

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N-cadherin-Presented Slit Repulsive-Cues Direct Collective Schwann cell Migration

Jj¹,

Harford-Wright²,

Wingfield-Digby³

et al. 2019

Preprint

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Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact-inhibition-of-locomotion (CIL), a local repulsive force, propels the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during Schwann cell collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin transhomodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin acts to traffic a repulsive Slit2/Slit3 signal to the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective SC migration, resulting in adherent, nonmigratory cell clusters. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration. ! 2! IntroductionTissue and organ morphogenesis requires the orchestration of the movement of large numbers of cells 1, 2 . In the adult, cell migration is less frequent but is important for aspects of tissue renewal and immune surveillance and can be activated following an injury, to contribute to wound healing and tissue-regeneration 3-6 . Moreover, these modes of migration are frequently recapitulated during pathologies such as cancer, allowing tumour cells to spread from their original site 3, 7, 8 .Peripheral nerve is one of the few tissues in the adult that retains the remarkable ability to regenerate following an injury 9-11 . We have previously shown that the successful regeneration of a transected nerve requires the collective migration of cords of Schwann cells (SCs) to transport regrowing axons the injury site 12 . Moreover, SC cords gain directionality across the wound, by migrating along a newly formed polarised vasculature, which develops prior to SC migration 13, 14 .However, SCs cultured alone exhibit contact inhibition of locomotion (CIL) 12 , a process where two cells repulse each other upon contact as a result of the inhibition of local protrusion formation and the repolarisation of the cells towards an alternative migration path [15][16][17][18] . Following an injury however, SC collective-migration is triggered following interactions with fibroblasts that come into contact with SCs as they enter the wound-site 12 . This heterotypic interaction with fibroblasts transforms SC behaviour from repulsive to attractive, a process mediated by ephrinB/EphB2signalling inducing a Sox2-mediated re-localisation of N-cadherin to the site of cell-cell junctions, resulting in their migration as cellular cords 12 . Consistent with this, we showed that in mice lacking EphB2 signalling (EphB2 -/-) both SC migration and axonal regeneration are impaired.Recently, CIL has b...

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Section: N-cadherin Is Required For Contact Inhibition Of Locomotion supporting

confidence: 77%

Section: Slit Is Required For the Efficient Collective Migration Of Smentioning

confidence: 99%

N-cadherin-Presented Slit Repulsive-Cues Direct Collective Schwann cell Migration

Jj¹,

Harford-Wright²,

Wingfield-Digby³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…(B) Overexpression of C3GF rescued Crk/Crkl deficiency-induced inhibition of cell proliferation. Cell investigate precise mechanisms that underlie the abnormal cell contact behavior (Fig 2B-D), a recent study reported that normal CIL relies on Fak and Src for coordinated redistribution of cell-matrix contacts and intracellular force in frog neural crest cells (Roycroft et al, 2018). Because Crk and Crkl mediate signals partly from Fak and Src (Shin et al, 2004;Birge et al, 2009;Watanabe et al, 2009), it is plausible that Crk and/or Crkl are also required for traction force redistribution, a key mechanism for repulsive locomotion as an essential feature of mesenchymal cells.…”

Section: Discussionmentioning

confidence: 99%

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

Imamoto

et al. 2020

Life Sci. Alliance

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CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore, Crk/Crkl deficiency sensitizes MEFs to 2-deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls.

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“…The importance of CiL for the migration of NC cells was demonstrated using Xenopus and zebrafish cephalic NC cells (Carmona-Fontaine et al 2008;Theveneau et al 2010;Mayor and Carmona-Fontaine 2010). Further evidence for CiL has been recently provided by Roycroft et al (2018), who showed how CiL could arise via the redistribution of adhesive forces through Src/FAK (steroid receptor coactivator and focal adhesion kinase). The existence and necessity of the opposite phenomenon, namely CoA, to ensure that the cells remain in a group, has been verified in Xenopus cephalic NC cells (Carmona-Fontaine et al 2011).…”

Section: Fixed Domainmentioning

confidence: 96%

Modelling collective cell migration: neural crest as a model paradigm

et al. 2019

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A huge variety of mathematical models have been used to investigate collective cell migration. The aim of this brief review is twofold: to present a number of modelling approaches that incorporate the key factors affecting cell migration, including cell-cell and cell-tissue interactions, as well as domain growth, and to showcase their application to model the migration of neural crest cells. We discuss the complementary strengths of microscale and macroscale models, and identify why it can be important to understand how these modelling approaches are related. We consider neural crest cell migration as a model paradigm to illustrate how the application of different mathematical modelling techniques, combined with experimental results, can provide new biological insights. We conclude by highlighting a number of future challenges for the mathematical modelling of neural crest cell migration.

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Redistribution of Adhesive Forces through Src/FAK Drives Contact Inhibition of Locomotion in Neural Crest

Cited by 38 publications

References 91 publications

N-cadherin-Presented Slit Repulsive-Cues Direct Collective Schwann cell Migration

N-cadherin-Presented Slit Repulsive-Cues Direct Collective Schwann cell Migration

Essential role of theCrkfamily-dosage in DiGeorge-like anomaly and metabolic homeostasis

Modelling collective cell migration: neural crest as a model paradigm

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