Editors' ChoiceDevelopmental Biology

Sox Keep Hair Follicle Stem Cells Cozy

Sci. Signal.  25 Feb 2014:
Vol. 7, Issue 314, pp. ec60
DOI: 10.1126/scisignal.2005209

Hair follicles cycle through proliferative (anagen), degenerative (catagen), and quiescent (telogen) phases. During anagen, resident hair-follicle stem cells (HFSCs) in the hair-follicle bulge compartment self-renew and divide to form the outer root sheath (ORS) and produce a population of transit-amplifying (TA) cells in the matrix compartment of the dermal papilla that ultimately gives rise to a hair. As the TA and ORS cells grow deeper into the skin, HFSCs become quiescent, and cells of the upper ORS form a new bulge. Kadaja et al. found that the transcription factor Sox9 is required for the cycling of HFSCs. Conditional knockout of Sox9 in HFSCs during telogen did not prevent cells from entering anagen but reduced the number of proliferating TA cells and prevented the regrowth of hair in shaved mice. Conditional knockout of Sox9 prevented HFSCs from reentering telogen and caused abnormal epidermal differentiation that disrupted bulge morphology and produced keratinized cysts that likely physically blocked the path of hair regrowth. Genome-wide chromatin immunoprecipitation of Sox9 in HFSCs and gene expression analyses of Sox9-deficient HFSCs revealed that Sox9 was required to inhibit the expression of genes encoding proteins involved in epidermal differentiation and to stimulate the expression of genes encoding proteins that promote self-renewal and those associated with activation of transforming growth factor–β (TGF-β) and Activin signaling. Conditional deletion of Sox9 in HFSCs reduced the abundance of phosphorylated Smad2 (similar to mothers against decapentaplegic 2), an effector of TGF-β and Activin signaling, which is normally increased in cells of the bulge during the telogen-to-anagen transition. Conditional knockout of the Activin receptor type 1B in HFSCs produced phenotypes similar to Sox9 loss of function. Cutaneous injection of Activin B restored Smad2 phosphorylation and partially rescued the hair-follicle phenotypes in mice with Sox9-deficient HFSCs. Thus, HFSCs use Sox9 to create signals that maintain self-renewal and prevent abnormal differentiation in their niche.

M. Kadaja, B. E. Keyes, M. Lin, H. A. Pasolli, M. Genander, L. Polak, N. Stokes, D. Zheng, E. Fuchs, SOX9: A stem cell transcriptional regulator of secreted niche signaling factors. Genes Dev. 28, 328–341 (2014). [PubMed]