ABSTRACT

The mechanisms that regulate cell-cycle arrest of cardiomyocytes during heart development are largely unknown. We have previously identified Tudor staphylococcal nuclease (Tudor-SN) as a cell-cycle regulator and have shown that its expression level was closely related to cell-proliferation capacity. Herein, we found that Tudor-SN was highly expressed in neonatal mouse myocardia, but it was lowly expressed in that of adults. Using Data Base of Transcription Start Sites (DBTSS), we revealed that Tudor-SN was a terminal oligo-pyrimidine (TOP) mRNA. We further confirmed that the translational efficiency of Tudor-SN mRNA was controlled by the mammalian target of rapamycin complex 1 (mTORC1) pathway, as revealed via inhibition of activated mTORC1 in primary neonatal mouse cardiomyocytes and activation of silenced mTORC1 in adult mouse myocardia; additionally, this result was recapitulated in H9c2 cells. We also demonstrated that the downregulation of Tudor-SN in adult myocardia was due to inactivation of the mTORC1 pathway to ensure that heart growth was in proportion to that of the rest of the body. Moreover, we revealed that Tudor-SN participated in the mTORC1-mediated regulation of cardiomyocytic proliferation, which further elucidated the correlation between Tudor-SN and the mTORC1 pathway. Taken together, our findings suggest that the translational efficiency of Tudor-SN is regulated by the mTORC1 pathway in myocardia and that Tudor-SN is involved in mTORC1-mediated regulation of cardiomyocytic proliferation and cardiac development.

摘要

在心脏发育过程中调节心肌细胞细胞周期停滞的机制在很大程度上是未知的。我们之前已将 Tudor 葡萄球菌核酸酶 (Tudor-SN) 鉴定为细胞周期调节剂，并表明其表达水平与细胞增殖能力密切相关。在这里，我们发现 Tudor-SN 在新生小鼠心肌中高表达，但在成年小鼠心肌中低表达。使用转录起始位点数据库 (DBTSS)，我们发现Tudor-SN是末端寡聚嘧啶 (TOP) mRNA。我们进一步证实了Tudor-SN的翻译效率mRNA 受哺乳动物雷帕霉素复合物 1 (mTORC1) 通路的靶点控制，这通过抑制原代新生小鼠心肌细胞中激活的 mTORC1 和成年小鼠心肌中沉默的 mTORC1 的激活来揭示；此外，该结果在 H9c2 细胞中重现。我们还证明了成人心肌中 Tudor-SN 的下调是由于 mTORC1 通路的失活，以确保心脏生长与身体其他部位的生长成比例。此外，我们揭示了Tudor-SN参与了mTORC1介导的心肌细胞增殖调节，这进一步阐明了Tudor-SN与mTORC1通路之间的相关性。综合起来，