Germ cell division and differentiation require intimate contact and interaction with the surrounding somatic cells. Luteinizing hormone (LH) triggers epidermal growth factor (EGF)-like growth factors to promote oocyte maturation and developmental competence by activating EGF receptor (EGFR) in somatic cells. Here, we showed that LH-EGFR signaling-activated sphingosine kinases (SphK) in somatic cells. The activation of EGFR by EGF increased S1P and calcium levels in cumulus-oocyte complexes (COCs), and decreased the binding affinity of natriuretic peptide receptor 2 (NPR2) for natriuretic peptide type C (NPPC) to release the cGMP-mediated meiotic arrest. These functions of EGF were blocked by the SphK inhibitor SKI-II, which could be reversed by the addition of S1P. S1P also activated the Akt/mTOR cascade reaction in oocytes and promoted targeting protein for Xklp2 (TPX2) accumulation and oocyte developmental competence. Specifically depleting Sphk1/2 in somatic cells reduced S1P levels and impaired oocyte meiotic maturation and developmental competence, resulting in complete female infertility. Collectively, SphK-produced S1P in somatic cells serves as a functional transmitter of LH-EGFR signaling from somatic cells to oocytes: acting on somatic cells to induce oocyte meiotic maturation, and acting on oocytes to improve oocyte developmental competence.

生殖细胞的分裂和分化需要与周围的体细胞密切接触和相互作用。黄体生成素 (LH) 触发表皮生长因子 (EGF) 样生长因子，通过激活体细胞中的 EGF 受体 (EGFR) 来促进卵母细胞成熟和发育能力。在这里，我们发现 LH-EGFR 信号激活体细胞中的鞘氨醇激酶 (SphK)。EGF 对 EGFR 的激活增加了卵丘-卵母细胞复合体 (COC) 中的 S1P 和钙水平，并降低了利钠肽受体 2 (NPR2) 对 C 型利钠肽 (NPPC) 的结合亲和力，从而释放了 cGMP 介导的减数分裂停滞。EGF 的这些功能被 SphK 抑制剂 SKI-II 阻断，这可以通过添加 S1P 来逆转。S1P 还激活了卵母细胞中的 Akt/mTOR 级联反应，并促进了 Xklp2 (TPX2) 积累和卵母细胞发育能力的靶向蛋白。特别耗尽体细胞中的Sphk1/2降低了 S1P 水平并损害了卵母细胞减数分裂成熟和发育能力，导致女性完全不育。总的来说，SphK 在体细胞中产生的 S1P 作为 LH-EGFR 信号从体细胞到卵母细胞的功能性递质：作用于体细胞以诱导卵母细胞减数分裂成熟，作用于卵母细胞以提高卵母细胞发育能力。