Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish.
Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish.
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DOI：
10.1242/dmm.023309
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发表时间：
2016-05-01
影响因子：
4.3
通讯作者：
Pack M
中科院分区：
文献类型：
--
作者：
Abrams J;Einhorn Z;Seiler C;Zong AB;Sweeney HL;Pack M
平滑肌收缩由肌球蛋白重链ATP酶（Myh 11）的调节活性控制。Myh 11突变在人类和动物模型的心血管、消化和泌尿生殖系统中具有不同的影响。我们以前报道了一个隐性错义突变，meltdown（mlt），它将高度保守的色氨酸精氨酸（W512 R）在斑马鱼Myh 11的刚性中继环。mlt突变破坏肌球蛋白调节，非自主诱导肠上皮细胞的侵入性扩张。在这里，我们报告了两个新发现的错义突变的开关-1（S237 Y）和卷曲螺旋（L1287 M）域的Myh 11，未能补充mlt。在两种纯合子突变体中均未检测到细胞侵袭，但可由氧化应激和致癌信号通路的激活诱导。由mlt和S237 Y突变引起的平滑肌缺陷也延迟了肠道运输，并改变了血管功能，如通过背主动脉中的血流所测量的。三个myh 11突变体诱导的细胞侵袭表型与肌球蛋白失调的程度相关。这些研究结果表明，脊椎动物的肠上皮细胞是调谐到周围基质的物理状态，这反过来又决定了其对生理和病理刺激的反应。改变平滑肌肌球蛋白调节的遗传变异可能是影响肠、脉管系统和其他含有表达平滑肌蛋白的平滑肌或收缩细胞的组织的疾病的风险因素，特别是在氧化还原应激的情况下。编辑选择：报道了在斑马鱼增强子-抑制子诱变筛选中发现的两个新鉴定的Myh 11基因错义突变。突变破坏肌球蛋白的调节和ATP酶的活性，在一个分级的方式，这与它们对肠道和血管生理的影响。
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.