SOX9: a stem cell transcriptional regulator of secreted niche signaling factors

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...

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Bibliographic Details
Published in:Genes & development 2014-02, Vol.28 (4), p.328-341
Main Authors: Kadaja, Meelis, Keyes, Brice E, Lin, Mingyan, Pasolli, H Amalia, Genander, Maria, Polak, Lisa, Stokes, Nicole, Zheng, Deyou, Fuchs, Elaine
Format: Article
Language:English
Subjects:
Activins - metabolism
Animals
Cell Differentiation
Cell Proliferation
Epidermis - cytology
Gene Expression Profiling
Gene Expression Regulation, Developmental
Hair Follicle - cytology
Hair Follicle - metabolism
Mice
Receptors, Notch - metabolism
Research Paper
Signal Transduction
Smad2 Protein - metabolism
SOX9 Transcription Factor - genetics
SOX9 Transcription Factor - metabolism
Stem Cells - cytology
Wnt Proteins - metabolism
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.233247.113