Granulosa Cell Ligand NPPC and Its Receptor NPR2 Maintain Meiotic Arrest in Mouse Oocytes

TLDR

Granulosa cells of mammalian Graafian follicles maintain oocytes in meiotic arrest, preventing precocious maturation. Mouse mural granulosa cells express Nppc mRNA while cumulus cells express its receptor NPR2, and oocyte‑derived paracrine factors upregulate Npr2 expression in cumulus cells. NPPC raises cGMP in cumulus cells and oocytes, blocking meiotic resumption in vitro, and loss of Nppc or Npr2 in mice leads to precocious meiosis, confirming that the NPPC–NPR2 axis maintains meiotic arrest essential for synchrony and fertility.

Abstract

Granulosa cells of mammalian Graafian follicles maintain oocytes in meiotic arrest, which prevents their precocious maturation. We show that mouse mural granulosa cells, which line the follicle wall, express natriuretic peptide precursor type C (Nppc) messenger RNA (mRNA), whereas cumulus cells surrounding oocytes express mRNA of the NPPC receptor NPR2, a guanylyl cyclase. NPPC increased cGMP levels in cumulus cells and oocytes and inhibited meiotic resumption in vitro. Meiotic arrest was not sustained in most Graafian follicles of Nppc or Npr2 mutant mice, and meiosis resumed precociously. Oocyte-derived paracrine factors promoted cumulus cell expression of Npr2 mRNA. Therefore, the granulosa cell ligand NPPC and its receptor NPR2 in cumulus cells prevent precocious meiotic maturation, which is critical for maturation and ovulation synchrony and for normal female fertility.