TY - JOUR
T1 - Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation
AU - Oshimori, Naoki
AU - Fuchs, Elaine
N1 - Funding Information:
We thank S. Karlsson for floxed-TβRII mice; D. Padua and S. Tavazoie for information about pSmad2 antibodies; N. Stokes and D. Oristian for in utero lentiviral injections and assistance in the mouse facility; S. Beronja and Y.C. Hsu for critical reading of the manuscript; and S. Williams, M. Schober, T. Chen, M. Kadaja, and other E.F. laboratory members for discussions. We appreciate the assistance of S. Mazel in the RU Flow Cytometry Resource Center, the Comparative Bioscience Center (an American Association of Accreditation of Laboratory Animal Care facility) for expert handling and care of the mice, and Memorial Sloan Kettering Genomics Core Facility for RNA and microarray processing. N.O. was supported by International Human Frontier Science Program Organization and is currently supported by the Japan Society for the Promotion of Science. E.F. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants to E.F. from National Institutes of Health (R01-AR050452) and Emerald Foundation.
PY - 2012/1/6
Y1 - 2012/1/6
N2 - Hair follicle (HF) regeneration begins when communication between quiescent epithelial stem cells (SCs) and underlying mesenchymal dermal papillae (DP) generates sufficient activating cues to overcome repressive BMP signals from surrounding niche cells. Here, we uncover a hitherto unrecognized DP transmitter, TGF-β2, which activates Smad2/3 transiently in HFSCs concomitant with entry into tissue regeneration. This signaling is critical: HFSCs that cannot sense TGF-β exhibit significant delays in HF regeneration, whereas exogenous TGF-β2 stimulates HFSCs in vivo and in vitro. By engineering TGF-β- and BMP-reporter mice, we show that TGF-β2 signaling antagonizes BMP signaling in HFSCs but not through competition for limiting Smad4-coactivator. Rather, our microarray, molecular, and genetic studies unveil Tmeff1 as a direct TGF-β2/Smad2/3 target gene, expressed by activated HFSCs and physiologically relevant in restricting and lowering BMP thresholds in the niche. Connecting BMP activity to an SC's response to TGF-βs may explain why these signaling factors wield such diverse cellular effects.
AB - Hair follicle (HF) regeneration begins when communication between quiescent epithelial stem cells (SCs) and underlying mesenchymal dermal papillae (DP) generates sufficient activating cues to overcome repressive BMP signals from surrounding niche cells. Here, we uncover a hitherto unrecognized DP transmitter, TGF-β2, which activates Smad2/3 transiently in HFSCs concomitant with entry into tissue regeneration. This signaling is critical: HFSCs that cannot sense TGF-β exhibit significant delays in HF regeneration, whereas exogenous TGF-β2 stimulates HFSCs in vivo and in vitro. By engineering TGF-β- and BMP-reporter mice, we show that TGF-β2 signaling antagonizes BMP signaling in HFSCs but not through competition for limiting Smad4-coactivator. Rather, our microarray, molecular, and genetic studies unveil Tmeff1 as a direct TGF-β2/Smad2/3 target gene, expressed by activated HFSCs and physiologically relevant in restricting and lowering BMP thresholds in the niche. Connecting BMP activity to an SC's response to TGF-βs may explain why these signaling factors wield such diverse cellular effects.
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U2 - 10.1016/j.stem.2011.11.005
DO - 10.1016/j.stem.2011.11.005
M3 - Article
C2 - 22226356
AN - SCOPUS:84855486150
SN - 1934-5909
VL - 10
SP - 63
EP - 75
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -