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(American Journal of Pathology. 2000;156:1041-1053.)
© 2000 American Society for Investigative Pathology

Regular Articles

New Roles for Glial Cell Line-Derived Neurotrophic Factor and Neurturin

Involvement in Hair Cycle Control

Natalia V. Botchkareva*, Vladimir A. Botchkarev*, Pia Welker*, Matti Airaksinen{dagger}, Wera Roth{ddagger}, Petro Suvanto{dagger}, Sven Müller-Röver*, Ina M. Hadshiew§, Christoph Peters{ddagger} and Ralf Paus*§

From the Department of Dermatology,*
Charité, Humboldt University, Berlin, Germany; the Institute of Biotechnology,{dagger}
University of Helsinki, Helsinki, Finland; the Institute of Molecular Medicine,{ddagger}
Albert-Ludwigs University, Freiburg, Germany; and the Department of Dermatology,§
University of Hamburg, Hamburg, Germany

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.




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