title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
abstract: Beare-Stevenson cutis gyrata syndrome (BSS) is a human genetic disorder characterized by skin and skull abnormalities. BSS is caused by mutations in the FGF receptor 2 (FGFR2), but the molecular mechanisms that induce skin and skull abnormalities are unclear. We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities. Fgfr2+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Wang
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhou
authors.forename: Kurun
authors.initials: K
authors.lastname: Oberoi
authors.forename: Robert
authors.initials: R
authors.lastname: Phelps
authors.forename: Ross
authors.initials: R
authors.lastname: Couwenhoven
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Amélie
authors.initials: A
authors.lastname: Rezza
authors.forename: Greg
authors.initials: G
authors.lastname: Holmes
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Percival
authors.forename: Jenna
authors.initials: J
authors.lastname: Friedenthal
authors.forename: Pavel
authors.initials: P
authors.lastname: Krejci
authors.forename: Joan T
authors.initials: JT
authors.lastname: Richtsmeier
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Michael
authors.initials: M
authors.lastname: Rendl
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
mesh_terms: D000015:Abnormalities, Multiple / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000052:Acanthosis Nigricans / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D003398:Craniosynostoses / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D012868:Skin Abnormalities / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012886:Skull / Q000002:abnormalities; D013577:Syndrome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048051:p38 Mitogen-Activated Protein Kinases