SphK-produced S1P in somatic cells is indispensable for LH-EGFR signaling-induced mouse oocyte maturation

Abstract Germ cells division and differentiation requires 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 show that LH-EGFR signaling activates sphingosine kinases (SphK1 and SphK2) of somatic cells to generate sphingosine-1-phosphate (S1P). S1P increases phospholamban (PLN) and calcium levels of cumulus cells and then decreases the binding affinity of natriuretic peptide receptor 2 (NPR2) for natriuretic peptide type C (NPPC), thus releasing the cGMP-mediated meiotic arrest. S1P also activates the Akt/mTOR cascade reaction in oocytes to promote targeting protein for Xklp2 (TPX2) accumulation and oocyte developmental competence. Specifically depleting Sphk1/2 in somatic cells reduces S1P levels and impairs 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.