Foxp1 and Foxp4 Deletion Causes the Loss of Follicle Stem Cell Niche and Cyclic Hair Shedding by Inducing Inner Bulge Cell Apoptosis

Quiescent hair follicle stem cells (HFSCs) reside in specialized bulge niche where they undergo activation and differentiation upon sensing niche-dependent signals during hair follicle (HF) homeostasis and wound repair. The underlying mechanism of HFSCs and bulge niche maintenance is poorly understood. Our previous study has reported that a transcription factor, forkhead box P1 (Foxp1), functions to maintain the quiescence of HFSCs. Here, we further discovered that forkhead box P4 (Foxp4), a close family member of Foxp1, had similar expression profiles in various components of HFs and formed a complex with Foxp1 in vitro and in vivo. The HF-specific deficiency of Foxp4 resulted in the precocious activation of HFSCs during hair cycles. In contrast to single Foxp1 or Foxp4 conditional knockout (cKO) mice, Foxp1/4 double cKO exerted an additive effect in the spectrum and severity of phenotypes in HFSC activation, hair cycling acceleration and hair loss, coupled with remarkable downregulation of fibroblast growth factor 18 (Fgf18) and bone morphogenetic protein 6 (Bmp6) expression in bulge cells. In addition, the double KO of Foxp1/4 induced the apoptosis of K6-positive (K6+) inner bulge cells, a well-established stem cell (SC) niche, thus resulting in the destruction of the bulge SC niche and recurrent hair loss. Our investigation reveals the synergistic role of Foxp1/4 in sustaining K6+ niche cells for the quiescence of HFSCs.