NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche.

TitleNFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche.
Publication TypeJournal Article
Year of Publication2013
AuthorsChang C-Y, H Pasolli A, Giannopoulou EG, Guasch G, Gronostajski RM, Elemento O, Fuchs E
Date Published2013 Mar 07
KeywordsAnimals, Apoptosis, Cell Differentiation, Cell Proliferation, Chromatin Immunoprecipitation, Endothelin-2, Epithelial Cells, Hair, Hair Color, Hair Follicle, Melanocytes, Mice, NFI Transcription Factors, Sequence Analysis, Stem Cell Factor, Stem Cell Niche, Stem Cells

Adult stem cells reside in specialized niches where they receive environmental cues to maintain tissue homeostasis. In mammals, the stem cell niche within hair follicles is home to epithelial hair follicle stem cells and melanocyte stem cells, which sustain cyclical bouts of hair regeneration and pigmentation. To generate pigmented hairs, synchrony is achieved such that upon initiation of a new hair cycle, stem cells of each type activate lineage commitment. Dissecting the inter-stem-cell crosstalk governing this intricate coordination has been difficult, because mutations affecting one lineage often affect the other. Here we identify transcription factor NFIB as an unanticipated coordinator of stem cell behaviour. Hair follicle stem-cell-specific conditional targeting of Nfib in mice uncouples stem cell synchrony. Remarkably, this happens not by perturbing hair cycle and follicle architecture, but rather by promoting melanocyte stem cell proliferation and differentiation. The early production of melanin is restricted to melanocyte stem cells at the niche base. Melanocyte stem cells more distant from the dermal papilla are unscathed, thereby preventing hair greying typical of melanocyte stem cell differentiation mutants. Furthermore, we pinpoint KIT-ligand as a dermal papilla signal promoting melanocyte stem cell differentiation. Additionally, through chromatin-immunoprecipitation with high-throughput-sequencing and transcriptional profiling, we identify endothelin 2 (Edn2) as an NFIB target aberrantly activated in NFIB-deficient hair follicle stem cells. Ectopically induced Edn2 recapitulates NFIB-deficient phenotypes in wild-type mice. Conversely, endothelin receptor antagonists and/or KIT blocking antibodies prevent precocious melanocyte stem cell differentiation in the NFIB-deficient niche. Our findings reveal how melanocyte and hair follicle stem cell behaviours maintain reliance upon cooperative factors within the niche, and how this can be uncoupled in injury, stress and disease states.

Alternate JournalNature
PubMed ID23389444
PubMed Central IDPMC3635831
Grant ListR01 HL080624 / HL / NHLBI NIH HHS / United States
R01-AR31737 / AR / NIAMS NIH HHS / United States
R01 AR031737 / AR / NIAMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 AR050452 / AR / NIAMS NIH HHS / United States
R01-HL080624 / HL / NHLBI NIH HHS / United States
R01-AR050452 / AR / NIAMS NIH HHS / United States