Epithelial growth control by neurotrophins: leads and lessons from the hair follicle.

Neurotrophins (NTs) exert many growth-regulatory functions beyond the nervous system. For example, murine hair follicles (HF) show developmentally and spatio-temporally stringently controlled expression of NTs, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4, and their cognate receptors, tyrosine kinase A-C (TrkA-C) and p75 neurotrophin receptor (p75NTR). Follicular NT and NT receptor expression exhibit significant, hair cycle-dependent fluctuations on the gene and protein level, which are mirrored by changes in nerve fiber density and neurotransmitter/neuropeptide content in the perifollicular neural networks. NT-3/TrkC and NGF/TrkA signaling stimulate HF development, while NT-3, NT-4 and BDNF inhibit the growth (anagen) of mature HF by the induction of apoptosis-driven HF regression (catagen). p75NTR stimulation inhibits HF development and stimulates catagen. Since the HF is thus both a prominent target and key peripheral source of NT, dissecting the role of NTs in the control of HF morphogenesis and cyclic remodeling provides a uniquely accessible, and easily manipulated, clinically relevant experimental model, which has many lessons to teach. Given that our most recent data also implicate NTs in human hair growth control, selective NT receptor agonists and antagonists may become innovative therapeutic tools for the management of hair growth disorders (alopecia, effluvium, hirsutism). Since, however, the same NT receptor agonists that inhibit hair growth (e.g., BDNF, NT-4) can actually stimulate epidermal keratinocyte proliferation, NT may exert differential effects on defined keratinocyte subpopulations. The studies reviewed here provide new clues to understanding the complex roles of NT in epithelial tissue biology and remodeling in vivo, and invite new applications for synthetic NT receptor ligands for the treatment of epithelial growth disorders, exploiting the HF as a lead model.