Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA.
Using conditional gene targeting in mice, we show that BMP receptor IA is essential for the differentiation of progenitor cells of the inner root sheath and hair shaft. Without BMPRIA activation, GATA-3 is down-regulated and its regulated control of IRS differentiation is compromised. In contrast, Lef1 is up-regulated, but its regulated control of hair differentiation is still blocked, and BMPRIA-null follicles fail to activate Lef1/beta-catenin-regulated genes, including keratin genes. Wnt-mediated transcriptional activation can be restored by transfecting BMPRIA-null keratinocytes with a constitutively activated beta-catenin. This places the block downstream from Lef1 expression but upstream from beta-catenin stabilization. Because mice lacking the BMP inhibitor Noggin fail to express Lef1, our findings support a model, whereby a sequential inhibition and then activation of BMPRIA is necessary to define a band of hair progenitor cells, which possess enough Lef1 and stabilized beta-catenin to activate the hair specific keratin genes and generate the hair shaft.
Kobielak
Krzysztof
K
Howard Hughes Medical Institute and Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10021-6399, USA.
Pasolli
H Amalia
HA
Alonso
Laura
L
Polak
Lisa
L
Fuchs
Elaine
E
D000818:Animals; D000831:Animals, Newborn; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004817:Epidermis / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D050990:GATA3 Transcription Factor; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018859:Hair Follicle / Q000002:abnormalities / Q000254:growth & development* / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000172:deficiency* / Q000235:genetics; D012868:Skin Abnormalities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013234:Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019737:Transplants; D014738:Vibrissae / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099176:Noggin Protein
D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D051821:Lymphoid Enhancer-Binding Factor 1; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099176:Noggin Protein; C495267:CTNNB1 protein, mouse; C494748:Gata3 protein, mouse; C497574:Lef1 protein, mouse