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Title: Enterocyte loss of polarity and gut wound healing rely upon the F-actin-severing function of villin

Author
item UBELMANN, FLORENT - Centre National De La Recherche Scientifique
item CHAMAILLARD, MATHIAS - Centre National De La Recherche Scientifique
item EL-MARJOU, FATIMA - Centre National De La Recherche Scientifique
item SIMON, ANTHONY - Centre National De La Recherche Scientifique
item NETTER, JEANNE - Centre National De La Recherche Scientifique
item VIGNJEVIC, DANIJELA - Centre National De La Recherche Scientifique
item NICHOLS, BUFORD - Children'S Nutrition Research Center (CNRC)
item QUEZADA-CALVILLO, ROBERTO - Centro De Investigacion
item GRANDJEAN, TEDDY - Centre National De La Recherche Scientifique
item LOUVARD, DANIEL - Centre National De La Recherche Scientifique
item REVENU, CELINE - Centre National De La Recherche Scientifique

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/22/2013
Publication Date: 3/21/2013
Citation: Ubelmann, F., Chamaillard, M., El-Marjou, F., Simon, A., Netter, J., Vignjevic, D., Nichols, B.L., Quezada-Calvillo, R., Grandjean, T., Louvard, D., Revenu, C. 2013. Enterocyte loss of polarity and gut wound healing rely upon the F-actin-severing function of villin. Proceedings of the National Academy of Sciences. 110(15):E1380-E1389.

Interpretive Summary: Inflammation of the small intestine is a frequent contributor to poor starch digestion and intolerance to dietary carbohydrates. Starch is normally broken down to simpler sugars by enzymes located on cells that line the inside of the gut. These enzymes function properly when they are located on the cell surface that face the inside of the gut. A common thread in various inflammation disorders is a failure of the enzymes to reach the correct surface of these gut cells. The mechanisms by which the newly produced enzymes are correctly positioned on the gut cell surface was studied in mice. It was shown that this positioning depended on particular protein machinery that existed within gut cells, and that this machinery was impaired during gut inflammation. These results help to explain the poor starch and sugar digestion that is seen in malnourished children, who usually suffer from inflamed small intestines.

Technical Abstract: Efficient wound healing is required to maintain the integrity of the intestinal epithelial barrier because of its constant exposure to a large variety of environmental stresses. This process implies a partial cell depolarization and the acquisition of a motile phenotype that involves rearrangements of the actin cytoskeleton. Here we address how polarized enterocytes harboring actin-rich apical microvilli undergo extensive cell remodeling to drive injury repair. Using live imaging technologies, we demonstrate that enterocytes in vitro and in vivo rapidly depolarize their microvilli at the wound edge. Through its F-actin-severing activity, the microvillar actin-binding protein villin drives both apical microvilli disassembly in vitro and in vivo and promotes lamellipodial extension. Photoactivation experiments indicate that microvillar actin is mobilized at the lamellipodium, allowing optimal migration. Finally, efficient repair of colonic mechanical injuries requires villin severing of F-actin, emphasizing the importance of villin function in intestinal homeostasis. Thus, villin severs F-actin to ensure microvillus depolarization and enterocyte remodeling upon injury. This work highlights the importance of specialized apical pole disassembly for the repolarization of epithelial cells initiating migration.