Zebrafish regenerate heart muscle through division of pre-existing cardiomyocytes. To discover underlying regulation, we assess transcriptome datasets for dynamic gene networks during heart regeneration and identify suppression of genes associated with the transcription factor Tp53. Cardiac damage leads to fluctuation of Tp53 protein levels, concomitant with induced expression of its central negative regulator, mdm2, in regenerating cardiomyocytes. Zebrafish lacking functional Tp53 display increased indicators of cardiomyocyte proliferation during regeneration, whereas transgenic Mdm2 blockade inhibits injury-induced cardiomyocyte proliferation. Induced myocardial overexpression of the mitogenic factors Nrg1 or Vegfaa in the absence of injury also upregulates mdm2 and suppresses Tp53 levels, and tp53 mutations augment the mitogenic effects of Nrg1. mdm2 induction is spatiotemporally associated with markers of de-differentiation in injury and growth contexts, suggesting a broad role in cardiogenesis. Our findings reveal myocardial Tp53 suppression by mitogen-induced Mdm2 as a regulatory component of innate cardiac regeneration.

斑马鱼通过预先存在的心肌细胞分裂来再生心肌。为了发现潜在的调控，我们评估心脏再生过程中动态基因网络的转录组数据集，并确定与转录因子Tp53相关的基因的抑制作用。心脏损伤导致Tp53蛋白水平的波动，同时在再生心肌细胞中诱导其中央负调节剂mdm2的表达。缺乏功能性Tp53的斑马鱼在再生过程中显示出增加的心肌细胞增殖指标，而转基因Mdm2阻滞抑制损伤诱导的心肌细胞增殖。在无损伤的情况下诱导心肌有丝分裂因子Nrg1或Vegfaa的过表达也上调了mdm2并抑制Tp53水平，而tp53突变则增强了Nrg1的促有丝分裂作用。mdm2诱导与损伤和生长环境中去分化的标志物在时空上相关，表明在心脏发生中具有广泛的作用。我们的发现揭示了有丝分裂原诱导的Mdm2作为先天性心脏再生的调节成分，可抑制心肌Tp53。