Ruvbl2 Suppresses Cardiomyocyte Proliferation During Zebrafish Heart Development and Regeneration.
Ruvbl2 Suppresses Cardiomyocyte Proliferation During Zebrafish Heart Development and Regeneration.
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DOI：
10.3389/fcell.2022.800594
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发表时间：
2022
影响因子：
5.5
通讯作者：
Burns CE
中科院分区：
文献类型：
--
作者：
Sharpe M;González-Rosa JM;Wranitz F;Jeffrey S;Copenhaver K;Burns CG;Burns CE
心肌细胞增殖是心脏发育和再生过程中新心肌的重要来源。因此，心肌细胞增殖驱动因子的突变会导致先天性心脏病，而梗塞的人类心脏会留下疤痕，因为心肌细胞在出生后退出细胞周期。为了促进心肌细胞增殖，在任何一种情况下，必须确定关键的调节因子。通过在斑马鱼中的ENU筛选，分离出了liebeslymmer（lik）突变体，并描述为在胚胎发生期间具有升高的心肌细胞数量。lik突变导致三个氨基酸插入到Ruvbl 2（一种高度保守的ATP酶）中。因为已经描述了Ruvbl 2样的功能获得和功能丧失特性，所以仍然不清楚Ruvbl 2是正调节还是负调节心肌细胞增殖。在这里，我们证明Ruvbl 2是斑马鱼心脏发育和再生过程中心肌细胞增殖的抑制因子。首先，我们证实了这样的推测，即ruvbl 2 lik/lik心脏中增加的心肌细胞数量是由过度增殖引起的。为了表征真正的ruvbl 2无效动物，我们创建了ruvbl 2基因座缺失等位基因（ruvbl 2 Δ）。与ruvbl 2 lik/lik突变体一样，ruvbl 2 Δ/Δ和复合杂合子ruvbl 2 lik/Δ动物显示心室增生，表明lik是功能缺失等位基因，并且ruvbl 2抑制心肌细胞增殖。这种活性是自主的，因为Ruvbl 2的组成性心肌过表达足以抑制对照心脏中的心肌细胞增殖并挽救在ruvbl 2 Δ/Δ突变心脏中观察到的过度增殖。最后，热休克诱导的Ruvbl 2过表达抑制心脏再生过程中的心肌细胞增殖并导致瘢痕形成。总之，我们的数据表明，Ruvbl 2功能自主作为斑马鱼心脏发育和成年心脏再生过程中的心肌细胞增殖的抑制剂。
Cardiomyocyte proliferation is an important source of new myocardium during heart development and regeneration. Consequently, mutations in drivers of cardiomyocyte proliferation cause congenital heart disease, and infarcted human hearts scar because cardiomyocytes exit the cell cycle postnatally. To boost cardiomyocyte proliferation in either setting, critical regulators must be identified. Through an ENU screen in zebrafish, the liebeskummer (lik) mutant was isolated and described as having elevated cardiomyocyte numbers during embryogenesis. The lik mutation results in a three amino acid insertion into Ruvbl2, a highly conserved ATPase. Because both gain- and loss-of-function properties have been described for ruvbl2 lik , it remains unclear whether Ruvbl2 positively or negatively regulates cardiomyocyte proliferation. Here, we demonstrate that Ruvbl2 is a suppressor of cardiomyocyte proliferation during zebrafish heart development and regeneration. First, we confirmed speculation that augmented cardiomyocyte numbers in ruvbl2 lik/lik hearts arise by hyperproliferation. To characterize bona fide ruvbl2 null animals, we created a ruvbl2 locus deletion allele (ruvbl2 Δ ). Like ruvbl2 lik/lik mutants, ruvbl2 Δ/Δ and compound heterozygote ruvbl2 lik/Δ animals display ventricular hyperplasia, demonstrating that lik is a loss of function allele and that ruvbl2 represses cardiomyocyte proliferation. This activity is autonomous because constitutive myocardial overexpression of Ruvbl2 is sufficient to suppress cardiomyocyte proliferation in control hearts and rescue the hyperproliferation observed in ruvbl2 Δ/Δ mutant hearts. Lastly, heat-shock inducible overexpression of Ruvbl2 suppresses cardiomyocyte proliferation during heart regeneration and leads to scarring. Together, our data demonstrate that Ruvbl2 functions autonomously as a suppressor of cardiomyocyte proliferation during both zebrafish heart development and adult heart regeneration.
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作者：
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