Dephosphorylation of juxtamembrane serines and threonines of the NPR2 guanylyl cyclase regulates oocyte meiotic resumption

Background The meiotic cell cycle of mammalian oocytes starts during embryogenesis and then pauses until luteinizing hormone (LH) restarts the cycle. This meiotic arrest is maintained by cGMP, which is produced in the granulosa cells by C-type natriuretic peptide (CNP) activation of NPR2 [1]. LH decreases cGMP in the granulosa cells, and via equilibration through gap junctions, cyclic GMP also decreases in the oocyte, thus releasing the meiotic arrest [2]. LH causes dephosphorylation and inactivation of NPR2 [3,4], but whether NPR2 dephosphorylation is required for meiotic resumption is not known. Seven regulatory NPR2 phosphorylation sites have been identified (Fig. 1) [5,6]. Here, we generated a knock-in mouse where each site was mutated to glutamate (Npr2-7E), resulting in a “constitutively phosphorylated” enzyme that we used to investigate the role of NPR2 dephosphorylation in the rapid resumption of meiosis in response to LH.