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Keratin 17 modulates hair follicle cycling in a TNF-dependent fashion

¹ Department of Biological Chemistry ² Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Mammalian hair follicles cycle between stages of rapid growth (anagen) and metabolic quiescence (telogen) throughout life. Transition from anagen to telogen involves an intermediate stage, catagen, consisting of a swift, apoptosis-driven involution of the lower half of the follicle. How catagen is coordinated, and spares the progenitor cells needed for anagen re-entry, is poorly understood. Keratin 17 (K17)-null mice develop alopecia in the first week post-birth, correlating with hair shaft fragility and untimely apoptosis in the hair bulb. Here we show that this abnormal apoptosis reflects premature entry into catagen. Of the proapoptotic challenges tested, K17-null skin keratinocytes in primary culture are selectively more sensitive to TNF. K17 interacts with TNF receptor 1 (TNFR1)-associated death domain protein (TRADD), a death adaptor essential for TNFR1-dependent signal relay, suggesting a functional link between this keratin and TNF signaling. The activity of NF-B, a downstream target of TNF, is increased in K17-null skin. We also find that TNF is required for a timely anagen–catagen transition in mouse pelage follicles, and that its ablation partially rescues the hair cycling defect of K17-null mice. These findings identify K17 and TNF as two novel and interdependent regulators of hair cycling.

[Keywords: Intermediate filament; hair cycle; apoptosis; anagen; catagen]

Received October 21, 2005; revised version accepted March 13, 2006.

E-MAIL coulombe{at}jhmi.edu; FAX (410) 614-7567.

Supplemental material is available at http://www.genesdev.org.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1387406

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