title: Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development.
abstract: Activating mutations in the KRAS oncogene are associated with three related human syndromes, which vary in hair and skin phenotypes depending on the involved allele. How variations in RAS signals are interpreted during hair and skin development is unknown. In this study, we investigated the developmental and transcriptional response of skin and hair to changes in RAS activity, using mouse genetic models and microarray analysis. While activation of Kras (Kras(G12D)) in the skin had strong effects on hair growth and hair shape, steady state changes in downstream RAS/MAPK effectors were subtle and detected only by transcriptional responses. To model the transcriptional response of multiple developmental pathways to active RAS, the effects of growth factor stimulation were studied in skin explants. Here FGF acutely suppressed Shh transcription within 90 min but had significantly less effect on Eda, WNT, Notch or BMP pathways. Furthermore, in vivo Fgfr2 loss-of-function in the ectoderm caused derepression of Shh, revealing a role for FGF in Shh regulation in the hair follicle. These studies define both dosage sensitive effects of RAS signaling on hair morphogenesis and reveal acute mechanisms for fine-tuning Shh levels in the hair follicle.
authors.affiliation: Division of Dermatology, Department of Medicine, Institute for Genomic Medicine, Stem Cell Program, University of California, 9500 Gilman Dr., MC-0869, La Jolla, San Diego, CA 92093-0869, USA.
authors.forename: Anandaroop
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Suguna Rani
authors.initials: SR
authors.lastname: Krishnaswami
authors.forename: Christopher
authors.initials: C
authors.lastname: Cowing-Zitron
authors.forename: Nai-Jung
authors.initials: NJ
authors.lastname: Hung
authors.forename: Heather
authors.initials: H
authors.lastname: Reilly-Rhoten
authors.forename: Julianne
authors.initials: J
authors.lastname: Burns
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Yu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018859:Hair Follicle / Q000166:cytology / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000254:growth & development / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)