Transforming growth factor-β is involved in maintaining oocyte meiotic arrest by promoting natriuretic peptide type C expression in mouse granulosa cells

Natriuretic peptide type C (NPPC) secreted by mural granulosa cells (MGCs) maintains oocyte meiotic arrest via the activation of guanylyl cyclase-linked natriuretic peptide receptor 2 (NPR2). Here, we investigated the effect of transforming growth factor (TGF)-beta on NPPC expression in MGCs and oocyte maturation. TGF-beta ligands (TGFB1 and TGFB3, but not TGFB2) and receptors (TGFBR1 and TGFBR2) were predominantly expressed in MGCs. The activation of the follicle-stimulating hormone (FSH) receptor by FSH/equine chorionic gonadotropin (eCG) increased the levels of TGFB1, TGFBR2, and TGF-beta downstream SMAD proteins in MGCs, which were decreased following the activation of the luteinizing hormone (LH) receptor by human chorionic gonadotropin (hCG). TGF-beta significantly increased the gene and protein levels of NPPC in cultured MGCs through SMAD3 binding to Nppc promoter regions. In the presence of FSH, TGF-beta further increased NPPC levels and inhibited oocyte meiotic resumption of cumulus-oocyte complexes (COCs). Moreover, Tgfbr2-specific depletion in granulosa cells using Fshr-Cre mice reduced NPPC mRNA and protein levels, resulting in the weak maintenance of oocyte meiotic arrest within large antral follicles. Tgfbr2 depletion also impaired follicle development, ovulation, and female fertility. Taken together, TGF-beta-promoted NPPC in MGCs is involved in maintaining oocyte meiotic arrest. FSH and LH could regulate NPPC levels in MGCs via TGF-beta and then control the process of oocyte meiosis.