Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis.
OBJECTIVE
The disruption of homeostasis between proliferation and apoptosis in the colonic epithelium contributes to the pathogenesis of human ulcerative colitis. Mice lacking the transcriptional corepressor myeloid translocation gene related-1 (Mtgr1) display impaired secretory cell lineage development in the small intestine and an increase in proliferation in the crypts of both the small and large intestines. Despite the increase in proliferating cells, the colons of Mtgr1-null mice have a normal cell lineage distribution and normal architecture. To uncover colonic phenotypes in Mtgr1(-/-) mice, we stressed the colonic epithelium with low-molecular-weight dextran sodium sulfate (DSS), which is a well-studied model of murine ulcerative colitis.


METHODS
Mtgr1-null mice were given 3% DSS in their drinking water for 4 days and the colons examined at various times thereafter for ulceration and for changes in proliferation and apoptosis.


RESULTS
Treatment with DSS resulted in severe colitis in Mtgr1(-/-) mice, at least partially due to increased epithelial apoptosis rates. Transplantation of wild-type and Mtgr1-null bone marrow into irradiated wild-type mice demonstrated that the severe DSS-induced ulceration seen in Mtgr1-null mice was due to a colonic, rather than a hematologic, defect. Importantly, the epithelium of DSS-treated Mtgr1-null mice failed to completely regenerate, showing changes consistent with chronic colitis, even 10 weeks after a single DSS treatment.


CONCLUSIONS
These findings suggest that Mtgr1 has an important role in crypt survival and regeneration after colonic epithelial ulceration.
Martinez
J Andres
JA
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Williams
Christopher S
CS
Amann
Joseph M
JM
Ellis
Tiffany C
TC
Moreno-Miralles
Isabel
I
Washington
M Kay
MK
Gregoli
Paul
P
Hiebert
Scott W
SW
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012720:Severity of Illness Index
C110408:CBFA2T2 myeloid-transforming gene-related protein; D010750:Phosphoproteins; D012097:Repressor Proteins; D012313:RNA; D016264:Dextran Sulfate