A cardiomyocyte-specific Wdr1 knockout demonstrates essential functional roles for actin disassembly during myocardial growth and maintenance in mice.
A cardiomyocyte-specific Wdr1 knockout demonstrates essential functional roles for actin disassembly during myocardial growth and maintenance in mice.
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DOI：
10.1016/j.ajpath.2014.04.007
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发表时间：
2014-07
期刊：
影响因子：
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通讯作者：
Baiyin Yuan;P. Wan;Dandan Chu;Junwei Nie;Yunshan Cao;Wen Luo;Shuangshuang Lu;Jiong Chen;Zhongzhou Yang
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文献类型：
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作者：
Baiyin Yuan;P. Wan;Dandan Chu;Junwei Nie;Yunshan Cao;Wen Luo;Shuangshuang Lu;Jiong Chen;Zhongzhou Yang
肌动蛋白动力学对肌肉发育和功能至关重要，导致肌动蛋白动力学失调的突变导致各种形式的遗传性肌肉疾病。AIP1是真核生物中肌动蛋白解聚因子/cofilin的主要辅助因子，促进肌动蛋白解聚因子/cofilin介导的肌动蛋白分解。它在脊椎动物肌肉中的功能尚不清楚。为了研究AIP1在心肌中的功能作用，我们制造了心肌细胞特异性缺失wdr1的条件敲除（cKO）小鼠，wdr1是酵母AIP1的哺乳动物同源物。Wdr1cKO小鼠在出生后第13天（P13）开始死亡，没有存活超过P24。在P12时，cKO小鼠表现出心肌肥厚和左心室收缩受损。心电图显示P10时心率降低，P波、T波异常，P12时QT间期延长。在cKO小鼠心肌中，肌动蛋白丝（F-actin）的积累始于P10，并在P12时变得突出。在肌原纤维中f -肌动蛋白聚集区域内，肌聚体成分α-肌动蛋白和原调节性蛋白-1表现出破坏模式，表明wdr1缺失引起的f -肌动蛋白聚集导致了肌聚体结构的破坏。异位cofilin与F-actin聚集体共定位。在成年小鼠中，wdr1缺失导致类似但更温和的心肌肥厚、肌原纤维内f -肌动蛋白积累和致死表型。综上所述，这些结果表明aip1调节的肌动蛋白动力学在小鼠心脏功能中起重要作用。
Actin dynamics are critical for muscle development and function, and mutations leading to deregulation of actin dynamics cause various forms of heritable muscle diseases. AIP1 is a major cofactor of the actin depolymerizing factor/cofilin in eukaryotes, promoting actin depolymerizing factor/cofilin-mediated actin disassembly. Its function in vertebrate muscle has been unknown. To investigate functional roles of AIP1 in myocardium, we generated conditional knockout (cKO) mice with cardiomyocyte-specific deletion ofWdr1, the mammalian homolog of yeastAIP1.Wdr1cKO mice began to die at postnatal day 13 (P13), and none survived past P24. At P12, cKO mice exhibited cardiac hypertrophy and impaired contraction of the left ventricle. Electrocardiography revealed reduced heart rate, abnormal P wave, and abnormal T wave at P10 and prolonged QT interval at P12. Actin filament (F-actin) accumulations began at P10 and became prominent at P12 in the myocardium of cKO mice. Within regions of F-actin accumulation in myofibrils, the sarcomeric components α-actinin and tropomodulin-1 exhibited disrupted patterns, indicating that F-actin accumulations caused byWdr1deletion result in disruption of sarcomeric structure. Ectopic cofilin colocalized with F-actin aggregates. In adult mice,Wdr1deletion resulted in similar but much milder phenotypes of heart hypertrophy, F-actin accumulations within myofibrils, and lethality. Taken together, these results demonstrate that AIP1-regulated actin dynamics play essential roles in heart function in mice.