Abstract
Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth.
Highlights
Hair follicles undergo recurrent cycles of growth, regression, and resting phases with a defined periodicity [1,2]
We demonstrate that miR-22 is an important posttranscriptional regulator that governs exit from anagen and maintenance of the hair follicle in telogen through inhibition of a transcriptional program driving keratinocyte proliferation, differentiation, and hair shaft assembly
At P17, miR-22 is strongly expressed throughout the hair follicle including both outer root sheath (ORS) and IRS, with the in-situ signal becoming weaker in the hair matrix (Fig 1)
Summary
Hair follicles undergo recurrent cycles of growth (anagen), regression (catagen), and resting (telogen) phases with a defined periodicity [1,2]. The hair follicle contains epithelial cells of the outer root sheath (ORS), matrix, the inner root sheath and hair shaft, and mesenchymal cells of dermal papilla [1,5]. Transit-amplifying matrix cells proliferate rapidly in response to signals from the dermal papilla after which they terminally differentiate to form the inner root sheath and hair shaft. The hair follicle rapidly degenerates and shortens until it is again adjacent to the hair follicle stem cell reservoir in the bulge region. This process may be triggered by a variety of stimuli, including apoptosis and loss of supportive growth factor signaling needed to maintain cell proliferation and differentiation during anagen [16]. While some apoptotic triggers promoting catagen have been defined, including Bcl2/Bax [17], p53 [18], p57 [19], and the transforming growth factors, TGF-β1 and TGF-β2 [20,21], little is known about how the stimulatory signals that drive anagen are terminated upon entry to catagen and maintained during telogen
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