Membrane‐bound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche

Morphogenesis, as illustrated by melanocyte migration and homing to the skin, requires cadherin adhesion, integrin‐dependent migration and Kit‐ligand growth factor signaling. However, it is not known how Kit ligand regulates integrin or cadherin‐dependent intraepidermal melanocyte behavior. To answer this question, we developed specific 2‐dimensional (2D) and 3D culture systems analyzing how soluble or immobilized Kit‐ligand‐regulated melanocyte migration on vitronectin and laminin, or within a monolayer of kidney epithelial cells. In a 2D system, soluble Kit ligand stimulated integrin‐dependent melanoblast migration and chemotaxis and accelerated integrin turnover. In contrast, immobilized, but not soluble, Kit ligand, enhanced integrin‐dependent melanocyte spreading on suboptimal laminin concentrations. In 3D, membrane‐bound Kit ligand induced intra‐epithelial melanocyte proliferation, survival, and tight adhesion to epithelial cells, while cleavable Kit ligand was less effective. In contrast, melanocyte motility was independent of membrane‐bound Kit ligand, but increased in the presence of the cleavable Kit‐ligand isoform. Trans‐membrane‐dimerization or basolateral‐targeting mutants of Kit ligand altered intraepithelial melanocyte localization, survival, and adhesion to epithelial cells. These data and the identification of c‐kit/Kit‐ligand clusters at cell contacts suggest that membrane‐bound Kit ligand captures cell surface‐expressed c‐kit, providing mechanical anchoring and survival signaling within intraepithelial niches, and thereby defining a new mechanism for melanocyte homeostasis and requirement for environmental niches.—Tabone‐Eglinger, S., Wehrle‐Haller, M., Aebischer, N., Jacquier, M.‐C., Wehrle‐Haller, B. Membranebound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche. FASEB J. 26, 3738–3753 (2012). www.fasebj.org