State-dependent signaling by Ca_v1.2 regulates hair follicle stem cell function

Abstract

The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Ca_v1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Ca_v1.2, they lack detectable voltage-dependent calcium currents. Ca_v1.2^TS acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Ca_v1.2 to induce anagen and overcome the TS phenotype. Ca_v1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.