Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice.
Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice.
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DOI：
10.1038/s41598-017-04823-1
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发表时间：
2017-06-30
影响因子：
4.6
通讯作者：
Mohri S
中科院分区：
文献类型：
--
作者：
Hashimoto K;Kodama A;Honda T;Hanashima A;Ujihara Y;Murayama T;Nishimatsu SI;Mohri S
在哺乳动物体内，胎儿心肌细胞在子宫内活跃增殖，形成原始心脏，但出生后不久就停止分裂。识别维持这种活跃的心肌细胞增殖的基本分子对于潜在的成人心脏再生是必不可少的。最近的一项研究表明，这种增殖依赖于出生时呼吸开始之前的低胎儿氧气条件。我们已经建立了一种小鼠胚胎心肌细胞的分离方案，在严格的低氧条件下进行，以模拟宫内环境，这是迄今为止报道的最高的增殖活性。分离/培养过程中的氧气暴露明显抑制细胞分裂和抑制促进细胞周期的基因，随后的全基因组分析证实Fam64a是一个新的调节分子。FAM64a在缺氧的胎儿心肌细胞核中大量表达，但在缺氧暴露后，这种表达被强烈地抑制，在出生后的心肌细胞中，随着呼吸的开始和由此引起的氧分压的升高，这种表达被显著抑制。FAM64A基因敲除抑制心肌细胞增殖，其过表达促进心肌细胞增殖。一个不可降解的Fam64a突变体的表达表明，在胚胎心肌细胞分裂过程中，最适的Fam64a表达和后期促进复合体/环体(APC/C)的降解是必要的。我们认为Fam64a是一种新的低氧胎鼠心肌细胞周期启动子。
Fetal cardiomyocytes actively proliferate to form the primitive heart in utero in mammals, but they stop dividing shortly after birth. The identification of essential molecules maintaining this active cardiomyocyte proliferation is indispensable for potential adult heart regeneration. A recent study has shown that this proliferation depends on a low fetal oxygen condition before the onset of breathing at birth. We have established an isolation protocol for mouse fetal cardiomyocytes, performed under strict low oxygen conditions to mimic the intrauterine environment, that gives the highest proliferative activities thus far reported. Oxygen exposure during isolation/culture markedly inhibited cell division and repressed cell cycle-promoting genes, and subsequent genome-wide analysis identified Fam64a as a novel regulatory molecule. Fam64a was abundantly expressed in hypoxic fetal cardiomyocyte nuclei, but this expression was drastically repressed by oxygen exposure, and in postnatal cardiomyocytes following the onset of breathing and the resulting elevation of oxygen tension. Fam64a knockdown inhibited and its overexpression enhanced cardiomyocyte proliferation. Expression of a non-degradable Fam64a mutant suggested that optimum Fam64a expression and subsequent degradation by anaphase-promoting complex/cyclosome (APC/C) during the metaphase-to-anaphase transition are required for fetal cardiomyocyte division. We propose that Fam64a is a novel cell cycle promoter of hypoxic fetal cardiomyocytes in mice.