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Published 6 November 2006. doi:10.1083/jcb.200602160
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 3, 505-514
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Article

 Conditional deletion of ß1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia, and early postnatal lethality

Robert G. Jones1,3,4, Xiufen Li1,4, Phillip D. Gray1,4, Jinqiu Kuang1,4, Frederic Clayton2,4, Wade S. Samowitz2, Blair B. Madison5, Deborah L. Gumucio5, and Scott K. Kuwada1,3,4

1 Huntsman Cancer Institute, 2 Department of Pathology, and 3 Department of Medicine, University of Utah, Salt Lake City, UT 84112
4 Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
5 Deptartment of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109

Correspondence to Scott K. Kuwada: scott.kuwada{at}hsc.utah.edu

Conditional deletion of ß1 integrins in the intestinal epithelium, unlike in epidermal and mammary epithelia, of mice does not result in decreased cell adhesion and proliferation, but instead causes a profound increase in epithelial proliferation with dysplasia and polypoid structures. The increased epithelial proliferation inhibited epithelial differentiation that caused severe malnutrition and early postnatal lethality. The striking similarities between ß1 integrin–deleted mice and neonatal mice with defective Hedgehog signaling led to the discovery that Hedgehog expression was markedly reduced in the former mice. ß1 integrins were found to drive the expression of Hedgehogs in intestinal epithelial cells in an HNF-3ß (Foxa2)–dependent fashion. The expression of Tcf-4, a transcription factor known to be required for intestinal epithelial stem cell proliferation, was increased and mislocalized in the intestinal epithelia of the ß1 integrin–deleted mice and in newborn mice treated with the Hedgehog signaling inhibitor cyclopamine. This study shows that ß1 integrins are key regulators of proliferation and homeostasis in the intestine and achieve this not through anchorage-dependent effects but by generating Hh expression and signaling.

Abbreviations used in this paper: ERK, extracellular signal–regulated kinase; G3PDH, glyceraldehyde-3-phosphate dehydrogenase; IEC, intestinal epithelial cell; NHE3, sodium hydrogen exchanger 3; P, postnatal day; RIE, rat intestinal epithelial.


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