Figure 3. The circadian clock modulates hair follicle regeneration.

(A) Circadian clock activity in the infundibulum and isthmus of hair follicles is similar to that of the interfollicular epidermis. In these progenitor/stem cell populations, the clock intrinsic to keratinocytes is required for diurnal variation in DNA replication. (B) There is heterogeneity in circadian output in bulge stem cells. High clock activity correlates with the high expression of WNT and TGFβ pathway genes, components of signaling pathways involved in stem cell activation. The functional consequence of clock-WNT/TGFβ connection is unclear, because deletion of Bmal1 within keratinocytes does not affect stem cell activation and timing of the first two hair growth cycles (Geyfman et al., 2012). Clock regulation of these signaling pathways, however, could affect the aging and cancer forming susceptibility of these stem cells. (C) Epithelial hair germ progenitors display prominent circadian activity prior to and during anagen onset. Whereas germline deletion of Bmal1 delays anagen initiation, such effects are not found in mice deleted for Bmal1 in keratinocytes. These findings suggest that the influence of the clock on anagen initiation is through other cell types, for example dermal papilla cells, or through more global regulation, such as modulation of systemic hormones that affect hair growth. (D) Silencing on clock genes in human hair follicles in vitro prolongs active growth phase. Due to technical limitations, the influence of the clock on other aspects of human hair follicle growth could not be studied. (E) During active growth phase in mouse hair follicles, circadian clock gates cell cycle progression in the epithelial matrix cells at the G2/M checkpoint. Administration of ionizing radiation to mice leads to more severe hair loss in the morning, during the mitotic peak.