Coordination by Cdc42 of actin, contractility, and adhesion for melanoblast movement in mouse skin

Woodham, E. F. et al. (2017) Coordination by Cdc42 of actin, contractility, and adhesion for melanoblast movement in mouse skin. Current Biology, 27(5), pp. 624-637. (doi: 10.1016/j.cub.2017.01.033) (PMID:28238662) (PMCID:PMC5344686)

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The individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large, bulky pseudopods with dynamic actin bursts. Despite assuming an elongated shape usually associated with fast mesenchymal motility, Cdc42 knockout melanoblasts migrated slowly and inefficiently in the epidermis, with nearly static pseudopods. Although much of the basic actin machinery was intact, Cdc42 null cells lacked the ability to polarize their Golgi and coordinate motility systems for efficient movement. Loss of Cdc42 de-coupled three main systems: actin assembly via the formin FMNL2 and Arp2/3, active myosin-II localization, and integrin-based adhesion dynamics.

Item Type:Articles
Additional Information:We acknowledge funding from Cancer Research UK (to L.M.M. [A17196], R.H.I. [A19257], and S.W.G.T.) and NIH grants P01-GM103723 and P41- EB002025 (to K.M.H.). N.R.P. is supported by a Pancreatic Cancer Research Fund grant (to L.M.M.). We thank Prof. Klemens Rottner for advice and for sharing unpublished FMNL2 constructs, and acknowledge funding to Prof. Rottner by the Deutsche Forschungsgemeinschaft (grant RO2414/3-2).
Glasgow Author(s) Enlighten ID:Tyrrell, Mr Benjamin and Spence, Dr Heather and Machesky, Professor Laura and Clark, Mr William and Giampazolias, Mr Evangelos and Insall, Professor Robert and Tait, Professor Stephen
Authors: Woodham, E. F., Paul, N. R., Tyrrell, B., Spence, H. J., Swaminathan, K., Scribner, M. R., Giampazolias, E., Hedley, A., Clark, W., Kage, F., Marston, D. J., Hahn, K. M., Tait, S. W.G., Larue, L., Brakebusch, C. H., Insall, R. H., and Machesky, L. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Current Biology
Publisher:Elsevier (Cell Press)
ISSN (Online):1879-0445
Published Online:23 February 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Current Biology 27(5): 624-637
Publisher Policy:Reproduced under a Creative Commons License

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