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 6

Topical p38 inhibition attenuates skin abnormalities in Fgfr2+/Y394C mice.

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Topical p38 inhibition attenuates skin abnormalities in Fgfr2+/Y394C mic...
The skin on the back of Fgfr2+/Y394C mice and littermate controls was treated with SB203580 or vehicle control. (A–D) H&E staining shows typical epidermal hyperplasia in Fgfr2+/Y394C mice treated with vehicle (A and B); SB203580 treatment rescued the skin phenotype in mutant mice (C and D). (E–H) Immunohistochemical staining of Ki67 shows increased number of Ki67-positive cells in the basal layer of vehicle-treated mutant mice (E and F); the hyperproliferation in the mutant epidermis was reduced after SB203580 treatment (G and H). (I–T) Immunohistochemical staining of differentiation markers of epidermis shows increased expression of the markers in the basal (K14, I, J, Q, and R) and spinous layers (K10, M, N, Q, and R) of vehicle-treated mutant mice; SB203580 treatment reduced the expression of these markers (K14, K, L, S, and T; K10, O, P, S, and T). Scale bars: 50 μm. (U and V) Bar graphs show that the epidermal thickening (U) and the increased number of Ki67-positive cells (V) of mutants were reversed after the SB203580 treatment. Results are presented as mean ± SEM. *P < 0.05; **P < 0.01.