A Role for P75 Neurotrophin Receptor in the Control of Hair Follicle Morphogenesis

During hair follicle (HF) morphogenesis, p75 neurotrophin receptor (p75NTR) reportedly is the first growth factor receptor found to be expressed by those fibroblasts that later develop into the dermal papilla (DP) of the HF. However, the functional role of p75NTR in HF morphogenesis is still unknown. Studying HF development in fetal and neonatal C57BL/6 murine back skin, we show that p75NTR-immunoreactivity (IR) is prominently expressed by DP fibroblasts as well as by skin nerves during the early steps of HF development. In contrast, p75NTR-IR disappears from the DP in the fully developed HF and it is expressed only in the epithelial outer root sheath of the HF. Compared to age-matched wild-type animals, p75NTR knockout (-/-) mice show significant acceleration of HF morphogenesis, and DP fibroblasts of p75NTR knockout mice show reduced proliferative activity in situ, indicating alterations in their transition from proliferation to differentiation. Although no significant differences in the expression of adhesion molecules (NCAM), selected morphogens (TGFbeta-2, HGF/SF, FGF-2, KGF), or their receptors (TGFbetaR-II, m-met, FGFR-1) were seen between DP of p75NTR knockout and wild-type mice, p75NTR mutants showed a prominent upregulation of FGFR-2, a high-affinity receptor for KGF, in both follicular DP and epithelium. Furthermore, the administration of anti-KGF neutralizing antibody significantly inhibited acceleration of HF morphogenesis in p75NTR knockout mice in vivo. These observations suggest that p75NTR plays an important role during HF morphogenesis, functioning as a receptor that negatively controls HF development, most likely via alterations in DP fibroblast proliferation/differentiation and via downregulation of KGF/FGFR-2 signaling in the HF.