Journal Article

p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice

Jabs, Ethylin Wang, Friedenthal, Jenna, Rezza, Amélie, Zhou, Xueyan, Sun, Miao, Holmes, Greg, Rendl, Michael, Wang, Yingli, Huso, David L., Krejci, Pavel, Richtsmeier, Joan T., Phelps, Robert, Oberoi, Kurun, Couwenhoven, Ross, Percival, Christopher J.

2012

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Abnormalities, Multiple - drug therapy / Abnormalities, Multiple - enzymology / Abnormalities, Multiple - genetics / Abnormalities, Multiple - pathology / Acanthosis Nigricans - drug therapy / Acanthosis Nigricans - enzymology / Acanthosis Nigricans - genetics / Acanthosis Nigricans - pathology / Amino Acid Substitution / Animals / Beare-Stevenson cutis gyrata syndrome / Biomedical research / Birth defects / Care and treatment / Cell growth / Craniosynostoses - drug therapy / Craniosynostoses - enzymology / Craniosynostoses - genetics / Craniosynostoses - pathology / Diagnosis / Humans / Hyperplasia / Kinases / Ligands / MAP Kinase Signaling System - drug effects / Mice / Mice, Transgenic / Mutation / Mutation, Missense / p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors / p38 Mitogen-Activated Protein Kinases - genetics / p38 Mitogen-Activated Protein Kinases - metabolism / Protein Kinase Inhibitors - pharmacology / Receptor, Fibroblast Growth Factor, Type 2 - genetics / Receptor, Fibroblast Growth Factor, Type 2 - metabolism / Skin Abnormalities - drug therapy / Skin Abnormalities - enzymology / Skin Abnormalities - genetics / Skin Abnormalities - pathology / Skull - abnormalities / Sutures / Syndrome / Transgenic animals