Clock genes, hair growth and aging

Abstract

Hair follicles undergo continuous cycles of growth, involution and rest. This process, referred to as the hair growth cycle, has a periodicity of weeks to months. At the same time, skin and hair follicles harbor a functional circadian clock that regulates gene expression with a periodicity of approximately twenty four hours. In our recent study we found that circadian clock genes play a role in regulation of the hair growth cycle during synchronized hair follicle cycling, uncovering an unexpected connection between these two timing systems within skin. This work, therefore, indicates a role for circadian clock genes in a cyclical process of much longer periodicity than twenty four hours.

Figure 1.. CLOCK-controlled gene expression in skin has a circadian pattern and correlates with synchronized hair growth cycles.

A schematic diagram showing rhythmic circadian expression of clock controlled gene Dbp over different phases of the hair growth cycle (solid line). The circadian amplitude of Dbp expression correlates with progression of the hair follicle cycle with highest expression during telogen (broken line). Skin histology for representative hair growth cycle stages is shown below. Note that this schematic does not show the actual length of each phase of the hair growth cycle.

Figure 2.. A model for how circadian clock genes participate in regulation of the synchronized hair growth cycle through regulation of cell cycle progression in the secondary hair germ.

The hair growth cycle (left panel) is a continuous process consisting of the quiescent telogen phase followed by the growth phase (anagen) where signals, presumably originating in the dermal papilla, activate stem and progenitor cell proliferation leading to growth and differentiation of the hair shaft. Anagen is followed by catagen where the lower two-thirds of the follicle undergo apoptosis, sparing the stem cell compartments and the dermal papilla. The CLOCK/BMAL1 complex is at the core of the mammalian circadian clock mechanism (right panel). It activates multiple genes, collectively referred to as clock controlled genes. Among these genes are Per1,2,3 and Cry1,2 whose protein products translocate into the nucleus to inhibit the transcriptional activity of the CLOCK/BMAL1 complex. Rev-erbα is another clock controlled gene whose protein product negatively regulates expression of Bmal1. Additionally, REV-ERBα directly inhibits expression of the G1-S cell cycle inhibitor p21^WAF1/CIP. In the absence of BMAL1, downregulation of Rev-erbα leads to high P21 expression and G1 arrest in the hair germ cells during anagen I of the hair follicle cycle, thus delaying anagen progression. APM - arrector pili muscle, Bu - bulge, CH - club hair, CTS - connective tissue sheath, DP - dermal papilla, EM - epithelial membrane, HS - hair shaft, IRS - inner root sheath, Ma - matrix, ORS - outer root sheath, SB - sebaceous gland, SHG - secondary hair germ.