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

Abstract

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.

The Mature COC Promotes the Ampullary NPPC Required for Sperm Release from Porcine Oviduct Cells

“…Interestingly, the immature COCs could not induce NPPC expression in the ampullae. The maturation of COCs is induced by LH-activated EGFR signaling in cumulus cells [ 10 , 11 ]. In our study, the activation of EGFR by EGF promoted TGFB1 expression in cumulus cells, and the addition of TGFB1 promoted NPPC expression in the ampullae.…”

“…During oestrus, luteinizing hormone (LH) from the pituitary acts on mural granulosa cells to induce the expression of epidermal growth factor (EGF)-like growth factors. Then, EGF receptor (EGFR) signaling is activated in cumulus cells, resulting in the maturation of COCs [ 10 , 11 ]. The mature COCs are picked up and transported into the oviductal ampulla for fertilization [ 12 ].…”

Interlukin-22 improves ovarian function in polycystic ovary syndrome independent of metabolic regulation: a mouse-based experimental study

“…Stat3 fl/fl mice and Fshr-Cre mice were kindly provided by Hua Yu from (Beckman Research Institute of City of Hope, CA) and Youqiang Su (Shandong University, Qingdao, China), respectively. Since the FSH receptor promoter is only expressed in granulosa cells, we generated granulosa cell-specific STAT3 knockout mice to better explore the specific mechanisms by which IL-22 affects granulosa cells by crossing Stat3 fl/fl mice with Fshr-Cre mice [ 15 ]. The mice were maintained under controlled temperature and lighting conditions (12-h light:12-h darkness cycle) with free access to food and water in a specific pathogen-free (SPF) facility.…”

SKI-349, a Sphingosine Kinases 1/2 Inhibitor, Suppresses Cell Viability, Invasion, and AKT/mTOR Signaling Pathway, and Shows Synergistic Cytotoxic Effects with Sorafenib in Hepatocellular Carcinoma

“…Our study found that SKI-349 inhibited the AKT/mTOR signaling pathway in HCC cell lines, which might be due to the fact that: (1) SKI-349 inhibited SPHK, which led to ceramide accumulation in HCC cells and activated phosphatases (including protein phosphatase 1 and protein phosphatase 2A), thus inactivating the AKT/mTOR cascade (Lin et al 2006). (2) As mentioned above, SKI-349 inhibited SPHK1 and SPHK2 activity (Hengst et al 2020); meanwhile, the decrease of SPHK1 and SPHK2 activity reduced S1P and further inhibit AKT/mTOR cascade reaction in HCC cell lines (Yuan et al 2022). Thus, SKI-349 was hypothesized to inhibit the AKT/mTOR signaling pathway by suppressing SPHK1-and SPHK2-regulated S1P.…”