Bone morphogenetic protein signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion.
Epithelial stem cells (EP-SCs) located in the bulge region of a hair follicle (HF) have the potential to give rise to hair follicle stem/progenitor cells that migrate down to regenerate HFs. Bone morphogenetic protein (BMP) signaling has been shown to regulate the HF cycle by inhibiting anagen induction. Here we show that active BMP signaling functions to prevent EP-SC activation and expansion. Dynamic expression of Noggin, a BMP antagonist, releases EP-SCs from BMP-mediated restriction, leading to EP-SC activation and initiation of the anagen phase. Experimentally induced conditional inactivation of the BMP type IA receptor (Bmpr1a) in EP-SCs leads to overproduction of HF stem/progenitor cells and the eventual formation of matricomas. This genetic manipulation of the BMP signaling pathway also reveals unexpected activation of beta-catenin, a major mediator of Wnt signaling. We propose that BMP activity controls the HF cycle by antagonizing Wnt/beta-catenin activity. This is at least partially achieved by BMP-mediated enhancement of transforming growth factor-beta-regulated epithelial cell-specific phosphatase (PTEN) function. Subsequently, PTEN, through phosphatidyl inositol 3-kinase-Akt, inhibits the activity of beta-catenin, the convergence point of the BMP and Wnt signaling pathways.
Zhang
Jiwang
J
Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, Missouri 64110, USA.
He
Xi C
XC
Tong
Wei-Gang
WG
Johnson
Teri
T
Wiedemann
Leanne M
LM
Mishina
Yuji
Y
Feng
Jian Q
JQ
Li
Linheng
L
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D018859:Hair Follicle / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D064547:Myxovirus Resistance Proteins; D009369:Neoplasms / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051176:beta Catenin / Q000378:metabolism; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004247:DNA; D019204:GTP-Binding Proteins; D019426:Integrases; D064547:Myxovirus Resistance Proteins; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C045073:Cre recombinase