Conditional deletion of beta1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia, and early postnatal lethality.
Conditional deletion of beta1 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 beta1 integrin-deleted mice and neonatal mice with defective Hedgehog signaling led to the discovery that Hedgehog expression was markedly reduced in the former mice. beta1 integrins were found to drive the expression of Hedgehogs in intestinal epithelial cells in an HNF-3beta (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 beta1 integrin-deleted mice and in newborn mice treated with the Hedgehog signaling inhibitor cyclopamine. This study shows that beta1 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.
Jones
Robert G
RG
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Li
Xiufen
X
Gray
Phillip D
PD
Kuang
Jinqiu
J
Clayton
Frederic
F
Samowitz
Wade S
WS
Madison
Blair B
BB
Gumucio
Deborah L
DL
Kuwada
Scott K
SK
D000818:Animals; D017209:Apoptosis; D018938:Caco-2 Cells; D002454:Cell Differentiation; D049109:Cell Proliferation; D020895:Enterocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005766:Gastrointestinal Contents / Q000737:chemistry; D017353:Gene Deletion; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D007422:Intestines / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D044342:Malnutrition / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D008871:Microvilli / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014162:Transfection
D053823:Hedgehog Proteins; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D012333:RNA, Messenger; C465570:Shh protein, mouse; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; C514061:ihh protein, mouse; C026615:villin; D051542:Hepatocyte Nuclear Factor 3-beta