p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice
Yingli Wang, … , Michael Rendl, Ethylin Wang Jabs
Yingli Wang, … , Michael Rendl, Ethylin Wang Jabs
Published May 15, 2012
Citation Information: J Clin Invest. 2012;122(6):2153-2164. https://doi.org/10.1172/JCI62644.
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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

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

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Figure 1

Fgfr2+/Y394C mice have cutis gyrata, acanthosis, skull synostosis, and other abnormalities.

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Fgfr2+/Y394C mice have cutis gyrata, acanthosis, skull synostosis, and ...
(A–D) Note skin furrows and hyperplasia in the mutant mice at P0 (A and B). With age, the skin phenotype becomes more obvious at P3 (C and D). (E–H) Surface reconstructions of HRCT images show midfacial hypoplasia of the mutant mice at P0. Note premature fusion of the coronal suture (E–H; black arrows), zygomaxillary suture (E–H; white arrows), and squamosal suture (E–H; red arrow) (Supplemental Table 1). (I and J) Alizarin red S and Alcian blue staining of the chest show abnormal bony fusion of sternum in mutant at P0. (K and L) Gross observations reveal protruding and enlarged umbilical stump in mutant (arrow). A, C, E, G, I, and K are from littermate controls. B, D, F, H, J, and L show the corresponding organs and tissues in mutant mice.