The mRNA-destabilizing protein Tristetraprolin targets “meiosis arrester” <i>Nppc</i> mRNA in mammalian preovulatory follicles

Abstract

C-natriuretic peptide (CNP) and its receptor guanylyl cyclase, natriuretic peptide receptor 2 (NPR2), are key regulators of cyclic guanosine monophosphate (cGMP) homeostasis. The CNP-NPR2-cGMP signaling cascade plays an important role in the progression of oocyte meiosis, which is essential for fertility in female mammals. In preovulatory ovarian follicles, the luteinizing hormone (LH)-induced decrease in CNP and its encoding messenger RNA (mRNA) natriuretic peptide precursor C (<i>Nppc</i>) are a prerequisite for oocyte meiotic resumption. However, it has never been determined how LH decreases CNP/<i>Nppc</i> In the present study, we identified that tristetraprolin (TTP), also known as zinc finger protein 36 (ZFP36), a ubiquitously expressed mRNA-destabilizing protein, is the critical mechanism that underlies the LH-induced decrease in <i>Nppc</i> mRNA. <i>Zfp36</i> mRNA was transiently up-regulated in mural granulosa cells (MGCs) in response to the LH surge. Loss- and gain-of-function analyses indicated that TTP is required for <i>Nppc</i> mRNA degradation in preovulatory MGCs by targeting the rare noncanonical AU-rich element harbored in the <i>Nppc</i> 3' UTR. Moreover, MGC-specific knockout of <i>Zfp36</i>, as well as lentivirus-mediated knockdown in vivo, impaired the LH/hCG-induced <i>Nppc</i> mRNA decline and oocyte meiotic resumption. Furthermore, we found that LH/hCG activates <i>Zfp36</i>/TTP expression through the EGFR-ERK1/2-dependent pathway. Our findings reveal a functional role of TTP-induced mRNA degradation, a global posttranscriptional regulation mechanism, in orchestrating the progression of oocyte meiosis. We also provided a mechanism for understanding CNP-dependent cGMP homeostasis in diverse cellular processes.