Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation.
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.
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA.
Naoki
N
Oshimori
Elaine
E
Fuchs
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019899:Paracrine Communication / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D053781:Transforming Growth Factor beta2