title: Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish.
abstract: Smooth muscle contraction is controlled by the regulated activity of the myosin heavy chain ATPase (Myh11). Myh11 mutations have diverse effects in the cardiovascular, digestive and genitourinary systems in humans and animal models. We previously reported a recessive missense mutation, meltdown (mlt), which converts a highly conserved tryptophan to arginine (W512R) in the rigid relay loop of zebrafish Myh11. The mlt mutation disrupts myosin regulation and non-autonomously induces invasive expansion of the intestinal epithelium. Here, we report two newly identified missense mutations in the switch-1 (S237Y) and coil-coiled (L1287M) domains of Myh11 that fail to complement mlt Cell invasion was not detected in either homozygous mutant but could be induced by oxidative stress and activation of oncogenic signaling pathways. The smooth muscle defect imparted by the mlt and S237Y mutations also delayed intestinal transit, and altered vascular function, as measured by blood flow in the dorsal aorta. The cell-invasion phenotype induced by the three myh11 mutants correlated with the degree of myosin deregulation. These findings suggest that the vertebrate intestinal epithelium is tuned to the physical state of the surrounding stroma, which, in turn, governs its response to physiologic and pathologic stimuli. Genetic variants that alter the regulation of smooth muscle myosin might be risk factors for diseases affecting the intestine, vasculature, and other tissues that contain smooth muscle or contractile cells that express smooth muscle proteins, particularly in the setting of redox stress.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Abrams
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zev
authors.initials: Z
authors.lastname: Einhorn
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Seiler
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zong
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA mpack@mail.med.upenn.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D059472:Exome / Q000235:genetics; D005769:Gastrointestinal Motility; D005799:Genes, Dominant; D005820:Genetic Testing; D006579:Heterozygote; D006720:Homozygote; D007422:Intestines / Q000033:anatomy & histology* / Q000098:blood supply* / Q000502:physiology; D009154:Mutation / Q000235:genetics; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; D018995:Myosin Heavy Chains; C000625349:myh11a protein, zebrafish
keywords: Intestine; Myosin; Smooth muscle; Zebrafish