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

Ectodermal appendage formation requires hedgehog (HH) signal reception, its conduction through the primary cilium and activation of Gli transcription factors (TF). How HH signalling induces cell-type-specific responses through Gli TF in stem cells (SCs) and their cilia-dependence remain open questions. Here, we use conditional mouse mutants to genetically dissect the roles of Gli and cilia HH mediators in the skin epithelium. Upon Gli2 depletion, hair follicle (HF) morphogenesis is delayed whereas sebaceous gland (SG) formation is enhanced, suggesting a dual role for Gli2 during appendage formation. By controlling proliferation of SG SCs, Gli2 impacts on the number and size of individual SG lobes. Whereas ablation of Gli3 shows no detectable phenotypes, HF cell fate is blocked in Gli2/3 double knockouts. In addition, loss of cilia phenocopies the loss of Gli2 but not the Gli2/3 mutants. Our study reveals that Gli3 exerts activator and cilia-independent functions in the absence of Gli2. Bullet pointsO_LIEpidermal Gli2 and Gli3 together mediate Hedgehog signalling and are essential for proper appendage formation C_LIO_LIGli3 activator function compensates for the loss of Gli2 during HF morphogenesis C_LIO_LIGli2 controls HF stem cell sub-compartments and SG formation C_LIO_LICilia mediate epidermal Gli2 but not Gli3 signalling in the skin epithelium C_LI