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4 BMP SIGNALLING REGULATES EPITHELIAL INTESTINAL CELL MIGRATION THROUGH SMAD5 TRANSCRIPTION FACTOR JF Schmouth, BA Auclair, A Zwinjsen, DL Gummucio, N Perreault BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily, which play crucial roles in embryogenesis, organogenesis and homeostasis in adult tissues. SMAD5 is a transcription factor implicated as a downstream signal mediator for several BMPs. Despite an increasing interest of BMP signalling in the gut biological process and pathologies, very little is known of the roles specifically played by SMAD5 in the gut morphogenesis.
CIHR group of Functional Development and Physiopathology of the Digestive Tract, University of Sherbrooke, Sherbrooke, Quebec
AIM: To investigate the in vivo function of SMAD5 in intestinal organogenesis and in intestinal epithelial cellular process such as proliferation, differentiation and migration.
METHODS AND RESULTS: With the use of the Cre/loxP system, we generated a mouse line with of SMAD5 exclusively deleted in the gut epithelium by crossing floxed SMAD5 mice with the Villin-Cre line. Immunostaining with SMAD5 antibody has shown specific loss of SMAD5 in the gut epithelium without influencing the mesenchymal compartment. Histological analysis revealed an elongation of the cryptal compartment and an important lengthening of the villi in the Villin-Cre/SMAD5loxP/loxP mice. Incorporation of BrdU during 90 min revealed no modifications in the number or localization of the proliferating cells in mutant mice. However, incorporation of BrdU during 48 h made it possible to highlight an increased speed in the migration of the epithelial cells along crypt/villus axis in the mutant animals. Immunostaining with an E-cadherin specific antibody showed a change of localization in the mutant mice. E-cadherin is normally found at zonula adherens establish in the lateral membrane of intestinal epithelial cells. In the floxed SMAD5 animals, we observed a relocalization of E-cadherin mainly to the basal membrane. Western blot analysis showed an increase in protein expression of E-cadherin in the mutant mice.
CONCLUSION: These results suggest that Smad5 may play an important role in intestinal epithelial migration by affecting E-cadherin localization.