Specific and redundant roles for Gli2 and Gli3 in establishing cell fate during murine hair follicle development.

Formation of skin epithelial appendages like hair follicles requires hedgehog (Hh) signal reception, its conduction through the primary cilium and activation of Gli transcription factors. How Hh signalling induces cell-type-specific responses through Gli transcription factors in hair follicle stem cells and their cilia-dependence remains unclear. Here, we use conditional mouse mutants to genetically dissect the roles of Gli2 and Gli3 transcription factors and cilia in the skin epithelium. Upon keratinocyte-specific depletion of Gli2, hair follicle morphogenesis is delayed whereas sebaceous gland formation is enhanced, suggesting a dual role for Gli2 during appendage development. Gli2 promotes proliferation of sebaceous gland stem cells, impacting the number and size of individual sebaceous gland lobes. While ablation of Gli3 shows no detectable phenotypes, hair follicle cell fate is blocked in Gli2/Gli3 double knockout (dKO) mice, suggesting functional compensation. Finally, loss of cilia phenocopies the depletion of Gli2 but not the Gli2/3 dKO mutants. Our study reveals compartment-specific regulation of murine skin morpohogenesis by Gli2 and cilia-independent activator functions of Gli3 in the absence of Gli2.