ZFIN ID: ZDB-PUB-160220-3
Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility, and vascular function in zebrafish
Abrams, J., Einhorn, Z., Seiler, C., Zong, A.B., Sweeney, H.L., Pack, M.
Date: 2016
Source: Disease models & mechanisms   9(5): 529-40 (Journal)
Registered Authors: Abrams, Joshua, Einhorn, Zev, Pack, Michael, Seiler, Christoph
Keywords: Myosin, Zebrafish, Intestine, Smooth muscle
MeSH Terms:
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Exome/genetics
  • Gastrointestinal Motility*
  • Genes, Dominant
  • Genetic Testing
  • Heterozygote
  • Homozygote
  • Intestines/anatomy & histology*
  • Intestines/blood supply*
  • Intestines/physiology
  • Mutation/genetics
  • Myosin Heavy Chains/chemistry
  • Myosin Heavy Chains/genetics
  • Myosin Heavy Chains/metabolism*
  • Neovascularization, Physiologic*
  • Oxidation-Reduction
  • Oxidative Stress
  • Sequence Analysis, DNA
  • Zebrafish/metabolism*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 26893369 Full text @ Dis. Model. Mech.
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ABSTRACT
Smooth muscle contraction is controlled by the regulated activity of the myosin heavy chain (Myh11) ATPase. 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) that 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 novel 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 regulation of smooth muscle myosin may 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.
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