The mRNA-destabilizing protein Tristetraprolin targets “meiosis arrester” Nppc 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 (Nppc) are a prerequisite for oocyte meiotic resumption. However, it has never been determined how LH decreases CNP/Nppc. 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 Nppc mRNA. Zfp36 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 Nppc mRNA degradation in preovulatory MGCs by targeting the rare noncanonical AU-rich element harbored in the Nppc 3′ UTR. Moreover, MGC-specific knockout of Zfp36, as well as lentivirus-mediated knockdown in vivo, impaired the LH/hCG-induced Nppc mRNA decline and oocyte meiotic resumption. Furthermore, we found that LH/hCG activates Zfp36/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.

SphK-produced S1P in somatic cells is indispensable for LH-EGFR signaling-induced mouse oocyte maturation

“…The elevation of intracellular calcium by S1P might also cause NPR2 inactivity by dephosphorylation 6,28 . The depletion of Sphk1/2 in granulosa cells could not block meiotic resumption of all oocytes within preovulatory follicles, possibly because the LH/hCG-induced decrease in NPPC levels in MGCs leads to a reduction in NPR2 function 29 .…”

SphK-produced S1P in somatic cells is indispensable for LH-EGFR signaling-induced mouse oocyte maturation

“…The elevation of intracellular calcium by S1P might also cause NPR2 inactivity by dephosphorylation [6,29]. The depletion of Sphk1/2 in granulosa cells could not block the meiotic resumption of all oocytes within preovulatory follicles, possibly because the LH/hCG-induced decrease in NPPC levels in MGCs leads to a reduction in NPR2 function [30].…”

A single cell atlas of the cycling murine ovary

“…We identified and prioritized four secreted biomarkers, expressed in mouse but also human ovaries, which varied significantly during different transitions of the estrous cycle, namely Inhba (78), Prss35 (60,79), Nppc (80,81), and Tinagl1 (82,83).…”

“…Finally, to take advantage of this rich dataset, we sought to identify secreted markers which varied in abundance during the estrous cycle and could thus be used as staging biomarkers in assisted reproduction. We identified and prioritized four secreted biomarkers, expressed in mouse but also human ovaries, which varied significantly during different transitions of the estrous cycle, namely Inhba (78), Prss35 (60,79), Nppc (80,81), and Tinagl1 (82,83).…”