Arresting Meiosis: In mammals, meiotic maturation of oocytes must be coordinated precisely with ovulation to produce a developmentally competent egg at the right time for fertilization. How is coordination achieved? Follicular granulosa cells prevent precocious resumption of meiosis in oocytes, maintaining meiotic arrest until the pre-ovulatory hormone surge. Granulosa cells produce cyclic guanosine monophosphate, which is delivered to oocytes and arrests meiotic progression by inhibiting oocyte cyclic adenosine monophosphate degradation. How cGMP production is regulated is unclear. Now, Zhang et al. (p. 366 ) report that NPPC (natriuretic peptide precursor type C), produced by mural granulosa cells, and its receptor NPR2, a guanylyl cyclase expressed by cumulus cells, together promote cGMP production by cumulus cells and are thus essential for maintaining meiotic arrest in mouse oocytes.

Natriuretic peptide type C (NPPC) and its cognate receptor natriuretic peptide receptor 2 (NPR2) are essential for maintaining meiotic arrest in mouse oocytes residing in Graafian follicles. Cumulus cells, which are associated with the oocyte, express the receptor NPR2, a guanylyl cyclase, whereas mural granulosa cells express ligand NPPC. This study determined the temporal expression of Npr2 and the hormonal factors that participate in regulating its expression and, thereby, in oocyte meiotic arrest. Stimulation of follicular development in vivo with equine chorionic gonadotropin (eCG) promoted expression of Npr2 mRNA by cumulus cells and some periantral mural granulosa cells. However, FSH did not elevate the levels of Npr2 mRNA in cultured cumulus-oocyte complexes (COCs) isolated from mice not stimulated in vivo with eCG. Nevertheless, estradiol elevated expression of this transcript in vitro to the same steady-state level found in COCs isolated from eCG-stimulated follicles in vivo. Expression of Npr2 mRNA was rapidly reduced in COCs in vitro after isolation from eCG-primed mice unless maintained in culture with estradiol. The ability of NPPC to maintain meiotic arrest in cultured COCs was transient unless culture was in estradiol-containing medium. Ability of cumulus cells to produce cyclic GMP, which is required for the maintenance of meiotic arrest, was also lost in the absence of estradiol, indicating that estradiol is required to maintain functional NPR2 receptors on cumulus cells in vitro. It is concluded that estradiol promotes and maintains expression of NPR2 in cumulus cells and participates in NPPC-mediated maintenance of oocyte meiotic arrest in vitro.

Fully grown mammalian oocytes are arrested at the first meiotic prophase until a surge of gonadotrophin at the mid-cycle. The actions of gonadotrophins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), on oocyte meiotic resumption are believed to be mediated in large part through increasing the production of cyclic adenosine 3′,5′-monophosphate and subsequent activation of mitogen-activated protein kinase (MAPK) in its surrounding cumulus granulosa cells. Recent findings indicate that gonadotrophins-induced epidermal growth factor-like growth factors, meiosis activating sterol and gonadal steroid hormones, possibly via protein kinase A II and protein kinase C pathways, are involved in the activation of MAPK. Another second messenger cyclic guanosine 3′,5′-monophosphate induced by nitric oxide or natriuretic peptides system mediates the function of gonadotrophins during oocyte meiotic resumption. FSH and LH induced pathways may either directly overlap or each hormone may utilize redundant pathways in oocyte maturation. A detailed appreciation of different FSH and LH-activated signaling pathways in mammalian oocytes will be needed in understanding their actions in follicular development and oocyte maturation.

In mammals, oocytes are arrested at the diplotene stage of meiosis I until the pre-ovulatory luteinizing hormone (LH) surge triggers meiotic resumption through the signals in follicular granulosa cells. In this study, we show that the estradiol (E2)-estrogen receptors (ERs) system in follicular granulosa cells has a dominant role in controlling oocyte meiotic resumption in mammals. We found that the expression of ERs was controlled by gonadotropins under physiological conditions. E2-ERs system was functional in maintaining oocyte meiotic arrest by regulating the expression of natriuretic peptide C and natriuretic peptide receptor 2 (NPPC/NPR2), which was achieved through binding to the promoter regions of Nppc and Npr2 genes directly. In ER knockout mice, meiotic arrest was not sustained by E2 in most cumulus–oocyte complexes in vitro and meiosis resumed precociously in pre-ovulatory follicles in vivo. In human granulosa cells, similar conclusions are reached that ER levels were controlled by gonadotropins and E2-ERs regulated the expression of NPPC/NPR2 levels. In addition, our results revealed that the different regulating patterns of follicle-stimulating hormone and LH on ER levels in vivo versus in vitro determined their distinct actions on oocyte maturation. Taken together, these findings suggest a critical role of E2-ERs system during oocyte meiotic progression and may propose a novel approach for oocyte in vitro maturation treatment in clinical practice.