LAUSR

Wnt signaling plays a pivotal role in regulating activation, proliferation, stem cell renewal and differentiation of hair follicle stem cells (HFSCs). Secreted frizzled related protein-1 (Sfrp1), a Wnt antagonist is up regulated in the HFSCs; however, its role in the HFSCs regulation is still obscure. Here, we show that Sfrp1 loss showed a depletion of HFSCs, enhanced HFSC proliferation and faster hair follicle cycle at PD21 to PD28, HFSC markers such as Lgr5 and Axin2 were decreased in both the Sfrp1  +/- and Sfrp1  -/- HFSCs. In addition, the second hair follicle cycle was also faster as compared to WT. Importantly, Sfrp1  -/- showed a restoration of HFSC by 2 nd telogen (PD49), while Sfrp1+/- did not show restoration with still having a decreased HFSC. Infact, restoration of HFSCs was due to a pronounced down-regulation of β-CATENIN activity mediated through a cross-talk of BMP-AKT-GSK3β signalling in Sfrp1-/- as compared to Sfrp1+/-, where down regulation was less pronounced. In cultured keratinocytes, Sfrp1 loss resulted in enhanced proliferation and clonogenicity, which were reversed by treating with either BMPR1A or GSK3β inhibitor thereby confirming BMP-AKT-GSK3β signaling involved in β-CATENIN regulation in both the Sfrp1  +/- and Sfrp1  -/- mice. Our study reveals a novel function of Sfrp1 by unravelling an in vivo molecular mechanism that regulate the HFSCs pool mediated through a hitherto unknown cross-talk of BMP-AKT-GSK3β signalling that maintain stem cell pool balance, which in turn maintain skin tissue homeostasis.