Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation.

[kindler syndrome]

Kindlin-1 is an integrin tail binding protein that controls integrin activation . Mutations in the FERMT-1 gene , which encodes for Kindlin-1 , lead to Kindler syndrome in man , which is characterized by skin blistering , premature skin aging and skin cancer of unknown etiology . Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments , which lead to hyperthickened epidermis , ectopic hair follicle development and increased skin tumor susceptibility . Mechanistically , Kindlin-1 controls keratinocyte adhesion through β 1 -class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α (v )β (6 ) integrin-mediated transforming growth factor -β (TGF-β ) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression . Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth -inhibitory signals and Wnt-β-catenin-mediated growth -promoting signals .