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 β type II receptor (TGF-βRII) 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-βRII. To prove that the defect observed in Elf3-null mice resulted from the lack of Elf3-dependent activation of Tgf-βRII expression, we performed a genetic rescue. Methods: We generated transgenic mice that express human TGF-βRII specifically in the intestinal epithelium under the control of the mouse A33 antigen promoter. Mice expressing the A33-TGF-βRII 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-βRII 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-βRII 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 β insensitivity.