Regeneration Next, Duke University, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Regeneration Next, Duke University, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cell Rep. 2020 Sep 1;32(9):108089. doi: 10.1016/j.celrep.2020.108089.
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.
斑马鱼通过已有心肌细胞的分裂来再生心肌。为了发现潜在的调控机制，我们评估了心脏再生过程中动态基因网络的转录组数据集，并鉴定出与转录因子 Tp53 相关的基因受到抑制。心脏损伤导致 Tp53 蛋白水平波动，同时在再生心肌细胞中诱导其核心负调控因子 mdm2 的表达。缺乏功能性 Tp53 的斑马鱼在再生过程中显示出心肌细胞增殖的增加指标，而转基因 Mdm2 阻断则抑制损伤诱导的心肌细胞增殖。在没有损伤的情况下，诱导心肌中促有丝分裂因子 Nrg1 或 Vegfaa 的过度表达也会上调 mdm2 并抑制 Tp53 水平，而 tp53 突变会增强 Nrg1 的促有丝分裂作用。mdm2 的诱导与损伤和生长环境中去分化标记物在时空上相关，提示其在心脏发生中具有广泛的作用。我们的研究结果揭示了心肌细胞中由有丝分裂原诱导的 Mdm2 对 Tp53 的抑制作用，这是心脏再生内在调节的一个组成部分。
