title: SOX9: a stem cell transcriptional regulator of secreted niche signaling factors.
abstract: Hair follicles (HFs) undergo cyclical periods of growth, which are fueled by stem cells (SCs) at the base of the resting follicle. HF-SC formation occurs during HF development and requires transcription factor SOX9. Whether and how SOX9 functions in HF-SC maintenance remain unknown. By conditionally targeting Sox9 in adult HF-SCs, we show that SOX9 is essential for maintaining them. SOX9-deficient HF-SCs still transition from quiescence to proliferation and launch the subsequent hair cycle. However, once activated, bulge HF-SCs begin to differentiate into epidermal cells, which naturally lack SOX9. In addition, as HF-SC numbers dwindle, outer root sheath production is not sustained, and HF downgrowth arrests prematurely. Probing the mechanism, we used RNA sequencing (RNA-seq) to identify SOX9-dependent transcriptional changes and chromatin immunoprecipitation (ChIP) and deep sequencing (ChIP-seq) to identify SOX9-bound genes in HF-SCs. Intriguingly, a large cohort of SOX9-sensitive targets encode extracellular factors, most notably enhancers of Activin/pSMAD2 signaling. Moreover, compromising Activin signaling recapitulates SOX9-dependent defects, and Activin partially rescues them. Overall, our findings reveal roles for SOX9 in regulating adult HF-SC maintenance and suppressing epidermal differentiation in the niche. In addition, our studies expose a role for SCs in coordinating their own behavior in part through non-cell-autonomous signaling within the niche.
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Meelis
authors.initials: M
authors.lastname: Kadaja
authors.forename: Brice E
authors.initials: BE
authors.lastname: Keyes
authors.forename: Mingyan
authors.initials: M
authors.lastname: Lin
authors.forename: H Amalia
authors.initials: HA
authors.lastname: Pasolli
authors.forename: Maria
authors.initials: M
authors.lastname: Genander
authors.forename: Lisa
authors.initials: L
authors.lastname: Polak
authors.forename: Nicole
authors.initials: N
authors.lastname: Stokes
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D000078404:Epidermal Cells; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018859:Hair Follicle / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D055758:SOX9 Transcription Factor; D051899:Smad2 Protein; C527933:Sox9 protein, mouse; D051153:Wnt Proteins; D028341:Activins
keywords: Activin; SOX9; hair follicle; skin; stem cells