Circadian clock genes contribute to the regulation of hair follicle cycling.

Kevin K Lin,Bogi Andersen,Padhraic Smyth,Ralf Paus,Mikhail Geyfman,Darya Chudova,Joseph S Takahashi,Alexander T Ihler,Vivek Kumar,Sarah E Millar

doi:10.1371/journal.pgen.1000573

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.

Highlights

Conserved hair follicle cycling is thought to provide mechanisms for controlling the length of hair in specific body sites, and to allow the periodic shedding of fur in response to seasonal changes in mammals [1]
We found a significant delay in anagen progression in both Clock and Bmal1 mutant mice, and the secondary hair germ cells within mutant hair follicles show decreased levels of phosphorylated Rb and lack mitotic cells, suggesting the circadian clock modulate anagen progression via its effect on the cell cycle
Probe sets with periodic profiles over the hair growth cycle were further narrowed to 6393 probe sets exhibiting periodic gene expression changes that cannot be explained by changes in tissue composition (Figure S1); we define this set of genes as hair cycleregulated genes (Figure 1B and Table S1)

Summary

Introduction

Conserved hair follicle cycling is thought to provide mechanisms for controlling the length of hair in specific body sites, and to allow the periodic shedding of fur in response to seasonal changes in mammals [1]. Hair follicle morphogenesis is completed around postnatal day (P) 14, at which time the follicle enters a phase called catagen. The stem cells become activated, likely in response to inductive signals from the dermal papilla, and the follicle enters the growth phase characterized by active keratinocyte proliferation and differentiation known as anagen. During the first two natural hair growth cycles in mice, the follicles of the dorsal skin are synchronized in progressing through the cycle, allowing the study of the mechanisms of natural hair follicle cycling. Tightly synchronized hair growth cycle can be initiated by depilation of hair shafts (e.g., waxing) during the telogen phase, with the caveat, of triggering an injury response [3]. Components of numerous molecular pathways, including TGFb/BMP family members and their antagonists, FGFs and steroid hormone receptors, have been implicated in the control of hair follicle cycling [1,4,5,6,7,8], the underlying mechanisms regulating its timing remain elusive [9]

Methods

Results

Conclusion