title: Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis.
abstract: The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA23298.
authors.forename: Nayden G
authors.initials: NG
authors.lastname: Naydenov
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA23298.
authors.forename: Alex
authors.initials: A
authors.lastname: Feygin
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA23298.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: John F
authors.initials: JF
authors.lastname: Kuemmerle
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, NY.
authors.forename: Gianni
authors.initials: G
authors.lastname: Harris
authors.affiliation: Laboratory of Molecular Cardiology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Conti
authors.affiliation: Laboratory of Molecular Cardiology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Adelstein
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA23298.|VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298.|Virginia Institute of Molecular Medicine, Richmond, VA 23298.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Ivanov
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D057167:Claudins / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D007070:Immunoglobulin A / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D024507:Nonmuscle Myosin Type IIA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D011391:Prolapse; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D057167:Claudins; C507360:Cldn7 protein, mouse; D016207:Cytokines; D007070:Immunoglobulin A; D020033:Protein Isoforms; D016264:Dextran Sulfate; D024507:Nonmuscle Myosin Type IIA