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

Background & Aims: ELF3, a member of the ETS transcription factor family, has been shown to transactivate the transforming growth factor beta type 11 receptor (TGF-beta RII) 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-beta RII. To prove that the defect observed in Elf3-null mice resulted from the lack of Elf3-dependent activation of Tgf-beta RII expression, we performed a genetic rescue. Methods: We generated transgenic mice that express human TGF-beta RII specifically in the intestinal epithelium under the control of the mouse A33 antigen promoter. Mice expressing the A33-TGF-beta RII 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-beta RII 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-beta RII 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.