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

<jats:title>Abstract</jats:title><jats:p>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)-β on NPPC expression in MGCs and oocyte maturation. TGF-β 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-β downstream SMAD proteins in MGCs, which were decreased following the activation of the luteinizing hormone (LH) receptor by human chorionic gonadotropin (hCG). TGF-β significantly increased the gene and protein levels of NPPC in cultured MGCs through SMAD3 binding to <jats:italic>Nppc</jats:italic> promoter regions. In the presence of FSH, TGF-β further increased NPPC levels and inhibited oocyte meiotic resumption of cumulus-oocyte complexes (COCs). Moreover, <jats:italic>Tgfbr2</jats:italic>-specific depletion in granulosa cells using <jats:italic>Fshr-Cre</jats:italic> mice reduced NPPC mRNA and protein levels, resulting in the weak maintenance of oocyte meiotic arrest within large antral follicles. <jats:italic>Tgfbr2</jats:italic> depletion also impaired follicle development, ovulation, and female fertility. Taken together, TGF-β-promoted NPPC in MGCs is involved in maintaining oocyte meiotic arrest. FSH and LH could regulate NPPC levels in MGCs via TGF-β and then control the process of oocyte meiosis.</jats:p>