title: Cortactin deficiency causes increased RhoA/ROCK1-dependent actomyosin contractility, intestinal epithelial barrier dysfunction, and disproportionately severe DSS-induced colitis.
abstract: The intestinal epithelium constitutes a first line of defense of the innate immune system. Epithelial dysfunction is a hallmark of intestinal disorders such as inflammatory bowel diseases (IBDs). The actin cytoskeleton controls epithelial barrier integrity but the function of actin regulators such as cortactin is poorly understood. Given that cortactin controls endothelial permeability, we hypothesized that cortactin is also important for epithelial barrier regulation. We found increased permeability in the colon of cortactin-KO mice that was accompanied by reduced levels of ZO-1, claudin-1, and E-cadherin. By contrast, claudin-2 was upregulated. Cortactin deficiency increased RhoA/ROCK1-dependent actomyosin contractility, and inhibition of ROCK1 rescued the barrier defect. Interestingly, cortactin deficiency caused increased epithelial proliferation without affecting apoptosis. KO mice did not develop spontaneous colitis, but were more susceptible to dextran sulfate sodium colitis and showed severe colon tissue damage and edema formation. KO mice with colitis displayed strong mucus deposition and goblet cell depletion. In healthy human colon tissues, cortactin co-localized with ZO-1 at epithelial cell contacts. In IBDs patients, we observed decreased cortactin levels and loss of co-localization with ZO-1. Thus, cortactin is a master regulator of intestinal epithelial barrier integrity in vivo and could serve as a suitable target for pharmacological intervention in IBDs.
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: A F
authors.initials: AF
authors.lastname: Citalán-Madrid
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: H
authors.initials: H
authors.lastname: Vargas-Robles
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: García-Ponce
authors.affiliation: Department of Infectomics and Molecular Pathogenesis, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Shibayama
authors.affiliation: Department of Infectomics and Molecular Pathogenesis, CINVESTAV-IPN, Mexico City, Mexico.|Consejo Nacional de Ciencia y Tecnología, Mexico City, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: Betanzos
authors.affiliation: Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: P
authors.initials: P
authors.lastname: Nava
authors.affiliation: Laboratory of Histology and Pathology, Faculty of Superior Studies Iztacala, UNAM, Mexico City, Mexico.
authors.forename: C
authors.initials: C
authors.lastname: Salinas-Lara
authors.affiliation: Division of Molecular Cell Biology, Zoological Institute, TU Braunschweig, Braunschweig, Germany.|Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rottner
authors.affiliation: Clinic for General and Visceral Surgery, University Clinic of Münster, Münster, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Mennigen
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Schnoor
mesh_terms: D000205:Actomyosin / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051356:Cortactin; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D000205:Actomyosin; D016264:Dextran Sulfate; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein