Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish
| Autor: | Michael Pack, Alan B. Zong, Zev Einhorn, Christoph Seiler, Joshua Abrams, H. Lee Sweeney |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Heterozygote Neuroscience (miscellaneous) Myosin lcsh:Medicine Medicine (miscellaneous) Neovascularization Physiologic medicine.disease_cause General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Dorsal aorta Immunology and Microbiology (miscellaneous) Smooth muscle lcsh:Pathology MYH11 medicine Animals Exome Amino Acid Sequence Genetic Testing Zebrafish Alleles Genes Dominant Mutation biology Myosin Heavy Chains lcsh:R Homozygote Heterozygote advantage Smooth muscle contraction Sequence Analysis DNA Zebrafish Proteins biology.organism_classification Zebra Intestinal epithelium Cell biology Intestine Intestines Oxidative Stress 030104 developmental biology Biochemistry Gastrointestinal Motility Oxidation-Reduction lcsh:RB1-214 Research Article |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 9, Iss 5, Pp 529-540 (2016) |
| ISSN: | 1754-8411 |
| Popis: | 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. Editors' choice: Two newly identified Myh11 gene missense mutations discovered in a zebrafish enhancer-suppressor mutagenesis screen are reported. The mutations disrupt myosin regulation and ATPase activity in a graded fashion, and this correlated with their effects on intestinal and vascular physiology. |
| Databáze: | OpenAIRE |
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