New roles for glial cell line-derived neurotrophic factor and neurturin -: Involvement in hair cycle control

Glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN), and their receptors, GDNF family receptor alpha-1. (GFR alpha-1) and GDNF family receptor alpha-2 (GFR alpha-2), are critically important for kidney and nervous system development. However, their role in skin biology, specifically in hair growth control, is as yet unknown. We have studied expression and function of GDNF, neurturin, GFR alpha-1, and GFR alpha-2 in murine skin during the cyclic transformation of the hair follicle (HF) from its resting state (telogen) to active growth (anagen) and then through regression (catagen) back to telogen. GDNF protein and GFR alpha-1 messenger RNA are prominently expressed in telogen skin, which lacks NTN and GFR alpha-2 transcripts. Early anagen development is accompanied by a significant decline in the skin content of GDNF protein and GFR alpha-1 transcripts. During the anagen-catagen transition, GDNF, GFR alpha-1, NTN, and GFR alpha-2 transcripts reach maximal levels. Compared with wild-type controls, GFR alpha-1 (+/-) and GFR alpha-2 (-/-) knockout mice show a significantly accelerated catagen development. Furthermore, GDNF or NTN administration significantly retards HF regression in organ-cultured mouse skin. This suggests important, previously unrecognized roles for GDNF/GFR alpha-1 and NTN/GFR alpha-2 signaling in skin biology, specifically in the control of apoptosis-driven HF involution, and raises the possibility that GFR alpha-1/GFR alpha-2 agonists/antagonists might become exploitable for the treatment of hair growth disorders that are related to abnormalities in catagen development.