TGF-betaRII rescues development of small intestinal epithelial cells in Elf3-deficient mice.
OBJECTIVE
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.
Flentjar
Nicole
N
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Chu
Po-Yin
PY
Ng
Annie Y-N
AY
Johnstone
Cameron N
CN
Heath
Joan K
JK
Ernst
Matthias
M
Hertzog
Paul J
PJ
Pritchard
Melanie A
MA
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020397:Goblet Cells / Q000166:cytology / Q000502:physiology*; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000166:cytology* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D012313:RNA / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C494436:Elf3 protein, mouse; C504395:Gpa33 protein, mouse; D008562:Membrane Glycoproteins; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II