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Gastroenterology. 2007 Apr;132(4):1410-9. Epub 2007 Feb 25.

TGF-betaRII rescues development of small intestinal epithelial cells in Elf3-deficient mice.

Author information

1
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.

Abstract

BACKGROUND & AIMS:

ELF3, a member of the ETS transcription factor family, has been shown to transactivate the transforming growth factor beta type II receptor (TGF-betaRII) promoter. Previously we showed that Elf3-null mice have a defect in the small intestine caused by a failure of small intestinal epithelial cells to differentiate and that these cells produced significantly lower levels of Tgf-betaRII. To prove that the defect observed in Elf3-null mice resulted from the lack of Elf3-dependent activation of Tgf-betaRII expression, we performed a genetic rescue.

METHODS:

We generated transgenic mice that express human TGF-betaRII specifically in the intestinal epithelium under the control of the mouse A33 antigen promoter. Mice expressing the A33-TGF-betaRII transgene were mated with Elf3(+/-) mice, and double heterozygous offspring harboring both the transgene and one mutant Elf3 allele were intercrossed.

RESULTS:

The resultant A33-TGF-betaRII transgenic Elf3(-/-) pups displayed normal small intestinal morphology, while the characteristic abnormality was retained in all Elf3(-/-) mice that did not express the transgene. This phenotypic rescue shows for the first time in vivo that a single gene, Elf3, is the critical upstream regulator of Tgf-betaRII in mouse small intestinal epithelium.

CONCLUSIONS:

This has important implications for our understanding of tissue-specific gene regulation and further strengthens the potential clinical connection between ELF3 and colorectal cancer involving transforming growth factor beta insensitivity.

PMID:
17408644
DOI:
10.1053/j.gastro.2007.02.054
[Indexed for MEDLINE]

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