Abstract
During mammalian oocyte growth, genomic DNA may accumulate DNA double-strand breaks (DSBs) induced by factors such as reactive oxygen species. Recent evidence demonstrated that slight DSBs do not activate DNA damage checkpoint proteins in denuded oocytes. These oocytes, even with DNA DSBs, can resume meiosis and progress to metaphase of meiosis II. Meiotic resumption in oocytes is also controlled by the surrounding cumulus cells; accordingly, we analyzed whether cumulus-cell enclosed oocytes (CEOs) with DNA damage are able to resume meiosis. Compared with DNA-damaged denuded oocytes, we found that meiotic resumption rates of CEOs significantly decreased. To assess the mechanism by which cumulus cells block meiotic resumption in CEOs with DNA DSBs, we treated the cumulus oocyte complex with the gap junction inhibitor carbenoxolone and found that carbenoxolone can rescue the block in CEO meiosis induced by DNA DSBs. Since cumulus cell-synthesized cAMPs can pass through the gap junctions between oocyte and cumulus cell to block oocyte meiosis, we measured the expression levels of adenylate cyclase 1 (Adcy1) in cumulus cells, and G-protein coupled receptor 3 (Gpr3) and phosphodiesterase 3A (Pde3a) in oocytes, and found that the mRNA expression level of Adcy1 increased significantly in DNA-damaged cumulus cells. In conclusion, our results indicate that DNA DSBs promote cAMP synthesis in cumulus cells, and cumulus cAMPs can inhibit meiotic resumption of CEOs through gap junctions.
Highlights
Mammalian oocytes initiate meiosis at the fetus stage, most oocytes become arrested at prophase of meiosis I a few days before or after birth[1]
Our study revealed that cumulus cells block the meiotic resumption of oocytes from cumulus oocyte complex (COC) containing DNA double-strand breaks by promoting cumulus cell cAMP synthesis
We found that cumulus cells control oocyte meiosis through gap junctions and the cAMP enriched in the zona pellucida and nucleus of double-strand breaks (DSBs) cumulus enclosed oocytes
Summary
Mammalian oocytes initiate meiosis at the fetus stage, most oocytes become arrested at prophase of meiosis I a few days before or after birth[1]. All growing oocytes remain arrested at prophase I and do not resume meiosis until oocyte growth is complete and corresponding follicles are stimulated by luteinizing hormone[2]. In comparison to somatic cells, oocytes are less sensitive to DNA DSBs. When the genomic DNA of denuded oocytes has slight double-strand breaks, oocytes do not activate DNA damage checkpoint proteins, and subsequently can resume meiosis, which was identified by germinal vesicle breakdown(GVBD), with damaged genome[8, 9]. Evidence shows that the second messenger cAMP is transferred from cumulus cells into oocytes through gap junctions [11, 12], and that elevated cAMP in oocytes maintains oocyte meiotic arrest [13]. We measured the mRNA levels of adenylate cyclase 1 (Adcy1) [16]in DNA damaged cumulus cells and Gpr3and Pde3ain oocytes
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