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First published online 24 July 2008
doi: 10.1242/dev.020453

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Fgf9 signaling regulates small intestinal elongation and mesenchymal development

Michael J. Geske¹, Xiuqin Zhang^2,*, Khushbu K. Patel¹, David M. Ornitz² and Thaddeus S. Stappenbeck^1,

¹ Departments of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
² Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.

Author for correspondence (e-mail: stappenb{at}pathology.wustl.edu)

Accepted 25 June 2008

Short bowel syndrome is an acquired condition in which the length of the small intestine is insufficient to perform its normal absorptive function. Current therapies are limited as the developmental mechanisms that normally regulate elongation of the small intestine are poorly understood. Here, we identify Fgf9 as an important epithelial-to-mesenchymal signal required for proper small intestinal morphogenesis. Mouse embryos that lack either Fgf9 or the mesenchymal receptors for Fgf9 contained a disproportionately shortened small intestine, decreased mesenchymal proliferation, premature differentiation of fibroblasts into myofibroblasts and significantly elevated Tgfβ signaling. These findings suggest that Fgf9 normally functions to repress Tgfβ signaling in these cells. In vivo, a small subset of mesenchymal cells expressed phospho-Erk and the secreted Tgfβ inhibitors Fst and Fstl1 in an Fgf9-dependent fashion. The p-Erk/Fst/Fstl1-expressing cells were most consistent with intestinal mesenchymal stem cells (iMSCs). We found that isolated iMSCs expressed p-Erk, Fst and Fstl1, and could repress the differentiation of intestinal myofibroblasts in co-culture. These data suggest a model in which epithelial-derived Fgf9 stimulates iMSCs that in turn regulate underlying mesenchymal fibroblast proliferation and differentiation at least in part through inhibition of Tgfβ signaling in the mesenchyme. Taken together, the interaction of FGF and TGFβ signaling pathways in the intestinal mesenchyme could represent novel targets for future short bowel syndrome therapies.

Key words: Fibroblast growth factor 9 (Fgf9), Gut development, Tgfβ signaling, Epithelial-mesenchymal crosstalk, Mesenchymal stem cells, Follistatin, Mouse

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