title: Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling.
abstract: Regenerative cycling of hair follicles offers an unique opportunity to explore the role of circadian clock in physiological tissue regeneration. We focused on the role of circadian clock in actively proliferating transient amplifying cells, as opposed to quiescent stem cells. We identified two key sites of peripheral circadian clock activity specific to regenerating anagen hair follicles, namely epithelial matrix and mesenchymal dermal papilla. We showed that peripheral circadian clock in epithelial matrix cells generates prominent daily mitotic rhythm. As a consequence of this mitotic rhythmicity, hairs grow faster in the morning than in the evening. Because cells are the most susceptible to DNA damage during mitosis, this cycle leads to a remarkable time-of-day-dependent sensitivity of growing hair follicles to genotoxic stress. Same doses of γ-radiation caused dramatic hair loss in wild-type mice when administered in the morning, during mitotic peak, compared with the evening, when hair loss is minimal. This diurnal radioprotective effect becomes lost in circadian mutants, consistent with asynchronous mitoses in their hair follicles. Clock coordinates cell cycle progression with genotoxic stress responses by synchronizing Cdc2/Cyclin B-mediated G2/M checkpoint. Our results uncover diurnal mitotic gating as the essential protective mechanism in highly proliferative hair follicles and offer strategies for minimizing or maximizing cytotoxicity of radiation therapies.
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Maksim V
authors.initials: MV
authors.lastname: Plikus
authors.forename: Christopher
authors.initials: C
authors.lastname: Vollmers
authors.forename: Damon
authors.initials: D
authors.lastname: de la Cruz
authors.forename: Amandine
authors.initials: A
authors.lastname: Chaix
authors.forename: Raul
authors.initials: R
authors.lastname: Ramos
authors.forename: Satchidananda
authors.initials: S
authors.lastname: Panda
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chuong
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D057906:Circadian Clocks / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology; D005720:Gamma Rays; D018859:Hair Follicle / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D056950:Period Circadian Proteins / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*
chemical_list: C538966:CRY2 protein, human; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D017931:DNA Primers; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins
keywords: hair cycle; proliferation; radiation therapy