Editors' ChoiceDevelopmental Biology

Assisting Arrest

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Science Signaling  19 Oct 2010:
Vol. 3, Issue 144, pp. ec320
DOI: 10.1126/scisignal.3144ec320

Mammalian oocytes arrest development at meiotic prophase until luteinizing hormone (LH) induces maturation before ovulation. Oocytes are surrounded by cumulus cells and enclosed in a follicle lined with mural granulosa cells (GCs); both cumulus cells and GCs are somatic in origin and required for maintaining meiotic arrest. Cyclic guanosine monophosphate (cGMP) produced in the somatic cells and delivered to the oocyte through gap junctions prevents meiotic progression by inhibiting an oocyte-specific phosphodiesterase that degrades cyclic adenosine monophosphate (cAMP). The natriuretic peptide precursor type C (NPPC) and the guanylyl cyclase natriuretic peptide receptor 2 (NPR2) have also been implicated in maintaining meiotic arrest. Zhang et al. report that, in the mouse, Nppc was expressed primarily in GCs, Npr2 was expressed primarily in cumulus cells, and follicles from Nppc or Npr2 mutant ovaries exhibited precocious development. Oocytes undergo spontaneous resumption of meiosis when cultured in the absence of GCs. Application of human NPPC to the culture medium prevented spontaneous development of oocytes that were surrounded by cumulus cells but did not prevent spontaneous development of denuded oocytes. NPPC application increased cGMP abundance in both cumulus cells and oocytes and increased cAMP in oocytes only. Removing oocytes from follicles reduced Npr2 expression in cumulus cells, but culturing these cumulus cells with denuded oocytes restored Npr2 expression, suggesting that a paracrine signal from the oocyte induced Npr2 expression in cumulus cells. Application of various combinations of purified GDF9 (growth and differentiation factor 9), BMP15 (bone morphogenetic protein 15), and FGF8B (fibroblast growth factor 8B), all of which are secreted by oocytes, also restored Npr2 expression in isolated cumulus cells, suggesting that these oocyte-derived growth factors may play a role in maintaining Npr2 expression in cumulus cells in vivo. The authors propose a model in which GC-derived NPPC activates NPR2 in cumulus cells, which stimulates production of cGMP that is then transferred to the oocyte, where it blocks cAMP degradation, thereby maintaining meiotic arrest.

M. Zhang, Y.-Q. Su, K. Sugiura, G. Xia, J. J. Eppig, Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science 330, 366–369 (2010). [Abstract] [Full Text]

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