Conditional deletion of β1 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 β1 integrin–deleted mice and neonatal mice with defective Hedgehog signaling led to the discovery that Hedgehog expression was markedly reduced in the former mice. β1 integrins were found to drive the expression of Hedgehogs in intestinal epithelial cells in an HNF-3β (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 β1 integrin–deleted mice and in newborn mice treated with the Hedgehog signaling inhibitor cyclopamine. This study shows that β1 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.
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6 November 2006
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November 06 2006
Conditional deletion of β1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia, and early postnatal lethality
Robert G. Jones,
Robert G. Jones
1Huntsman Cancer Institute
3Department of Medicine, University of Utah, Salt Lake City, UT 84112
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
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Xiufen Li,
Xiufen Li
1Huntsman Cancer Institute
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
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Phillip D. Gray,
Phillip D. Gray
1Huntsman Cancer Institute
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
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Jinqiu Kuang,
Jinqiu Kuang
1Huntsman Cancer Institute
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
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Frederic Clayton,
Frederic Clayton
2Department of Pathology,
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
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Wade S. Samowitz,
Wade S. Samowitz
2Department of Pathology,
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Blair B. Madison,
Blair B. Madison
5Deptartment of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
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Deborah L. Gumucio,
Deborah L. Gumucio
5Deptartment of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
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Scott K. Kuwada
Scott K. Kuwada
1Huntsman Cancer Institute
3Department of Medicine, University of Utah, Salt Lake City, UT 84112
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
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Robert G. Jones
1Huntsman Cancer Institute
3Department of Medicine, University of Utah, Salt Lake City, UT 84112
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
Xiufen Li
1Huntsman Cancer Institute
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
Phillip D. Gray
1Huntsman Cancer Institute
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
Jinqiu Kuang
1Huntsman Cancer Institute
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
Frederic Clayton
2Department of Pathology,
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
Wade S. Samowitz
2Department of Pathology,
Blair B. Madison
5Deptartment of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
Deborah L. Gumucio
5Deptartment of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
Scott K. Kuwada
1Huntsman Cancer Institute
3Department of Medicine, University of Utah, Salt Lake City, UT 84112
4Salt Lake City Veterans Administration Health Care System, Salt Lake City, UT 84112
Correspondence to Scott K. Kuwada: [email protected]
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.
Received:
February 28 2006
Accepted:
October 06 2006
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2006
J Cell Biol (2006) 175 (3): 505–514.
Article history
Received:
February 28 2006
Accepted:
October 06 2006
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Citation
Robert G. Jones, Xiufen Li, Phillip D. Gray, Jinqiu Kuang, Frederic Clayton, Wade S. Samowitz, Blair B. Madison, Deborah L. Gumucio, Scott K. Kuwada; Conditional deletion of β1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia, and early postnatal lethality . J Cell Biol 6 November 2006; 175 (3): 505–514. doi: https://doi.org/10.1083/jcb.200602160
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