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 intraepithelial 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. Transmembrane-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.
Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.
Severine
S
Tabone-Eglinger
Monique
M
Wehrle-Haller
Nicole
N
Aebischer
Marie-Claude
MC
Jacquier
Bernhard
B
Wehrle-Haller
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D061985:Madin Darby Canine Kidney Cells; D008544:Melanocytes / Q000166:cytology*; D051379:Mice; D008969:Molecular Sequence Data; D019089:Stem Cell Factor / Q000502:physiology*
D017077:Culture Media, Conditioned; D019089:Stem Cell Factor