Circadian Clock Genes Contribute to the Regulation of Hair Follicle Cycling

Abstract

Hair follicles undergo recurrent cycling of controlled growth (anagen), regression (catagen), and relative quiescence (telogen) with a defined periodicity. Taking a genomics approach to study gene expression during synchronized mouse hair follicle cycling, we discovered that, in addition to circadian fluctuation, CLOCK–regulated genes are also modulated in phase with the hair growth cycle. During telogen and early anagen, circadian clock genes are prominently expressed in the secondary hair germ, which contains precursor cells for the growing follicle. Analysis of Clock and Bmal1 mutant mice reveals a delay in anagen progression, and the secondary hair germ cells show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting that circadian clock genes regulate anagen progression via their effect on the cell cycle. Consistent with a block at the G1 phase of the cell cycle, we show a significant upregulation of p21 in Bmal1 mutant skin. While circadian clock mechanisms have been implicated in a variety of diurnal biological processes, our findings indicate that circadian clock genes may be utilized to modulate the progression of non-diurnal cyclic processes.

Author Summary

The hair follicle renews itself by repeatedly cycling among growth, regression, and rest phases. One function of hair follicle cycling is to allow seasonal changes in hair growth. Understanding the regulation of hair follicle cycling is also of interest because abnormal regulation of hair cycle control genes is responsible for several types of human hair growth disorders and skin cancers. We report here that Clock and Bmal1 genes, which control circadian rhythms, are also important for the regulation of hair follicle cycling, a biological process of much longer duration than 24 hours. Detailed analysis of skin from mice mutated for central clock genes indicates a significant delay in the progression of the hair growth phase. We show that clock genes affect the expression of key cell cycle control genes and that keratinocytes in a critical compartment of the hair follicles in Bmal1 mutant mice are halted in the G1 phase of the cell cycle. These findings provide novel insight into circadian control mechanisms in modulating the progression of cyclic biological processes on different time scales.