Abstract
ABSTRACTSmooth 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.
Highlights
Smooth muscle in the vertebrate intestine is arranged in discrete layers surrounding the epithelium (Sanders et al, 2012)
MYH11 variants detected via exome sequencing To determine whether human orthologs of the zebrafish myh11 mutations have been detected in genome-sequencing projects, we reviewed the location and frequency of MYH11 variants listed in the Exome Aggregation Consortium (ExAc) browser
In previous work, we showed that smooth muscle myosin carrying a missense mutation in the Myh11 rigid relay loop, myh11mlt, had non-regulated, actin-independent ATPase activity
Summary
Smooth muscle in the vertebrate intestine is arranged in discrete layers surrounding the epithelium (Sanders et al, 2012). Mutations that disrupt smooth muscle contractile function have pronounced effects on digestive physiology and are a cause of heritable digestive disease (Gauthier et al, 2014; He et al, 2008; Thorson et al, 2014; Wang et al, 2010; Wangler et al, 2014)
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