Abstract
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.
Highlights
Fetal cardiomyocytes actively proliferate in utero in mammals to form the primitive heart, but they stop dividing soon after birth and switch to hypertrophic growth
Our findings identify a novel O2-dependent and hypoxia inducible factor-1α (Hif-1α)-independent system that is essential for Fetal cardiomyocytes (fCMs) proliferation at the late embryonic stage
We used fCMs mainly at the E16–E18 stage to elucidate the molecular mechanism of fCM proliferation at the late embryonic stage
Summary
Fetal cardiomyocytes (fCMs) actively proliferate in utero in mammals to form the primitive heart, but they stop dividing soon after birth and switch to hypertrophic growth. To the best of our knowledge, this cell division rate is the highest yet reported for mouse CMs. We cultured late embryonic fCMs (E16–E18) using this culture system and were able to identify Fam64a (family with sequence similarity 64, member A, known as Rcs1) as the essential molecule for fCM proliferation. We report that Fam64a is indispensable for fCM proliferation, where its optimum expression and degradation by the APC/C are both required for the cell cycle to progress. This degradation occurs during the metaphase-to-anaphase transition, which is an earlier time point than is seen in HeLa cells. Our findings identify a novel O2-dependent and Hif-1α-independent system that is essential for fCM proliferation at the late embryonic stage
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