The mRNA-destabilizing protein Tristetraprolin targets “meiosis arrester” Nppc mRNA in mammalian preovulatory follicles-猫眼课题宝

DOI：

10.1073/pnas.2018345118

发表时间：

2021-05

期刊：

Proceedings of the National Academy of Sciences

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Guangyin Xi;L. An;Wenjing Wang;Jing Hao;Qianying Yang;Lizhu Ma;Jinlun Lu;Yue Wang;Wenjuan Wang;Wei Zhao;Juan Liu;Mingyao Yang;Xiaodong Wang;Zhenni Zhang;Chao Zhang;Meiqiang Chu;Yuan Yue;Fusheng Yao;Meijia Zhang;Jianhui Tian

雌性哺乳动物的生育能力取决于卵母细胞减数分裂的良好协调进程，这是雌性生殖细胞分裂，对单倍体卵母细胞的形成至关重要。在排卵前卵泡中，LH如何诱导CNP及其编码mRNA Nppc的减少，这是卵母细胞减数分裂恢复的先决条件，仍然是理解控制卵母细胞减数分裂的机制的一个悬而未决的问题。目前的研究表明，TTP，mRNA的不稳定蛋白，是负责LH诱导的Nppc mRNA的快速下降和卵母细胞减数分裂恢复的调节成分之一。这一发现不仅突出了卵泡外周转录后调控对微调卵母细胞减数分裂的重要性，而且还提供了对其他生理系统中CNP依赖性cGMP稳态的深入了解。C-利钠肽（CNP）及其受体鸟苷酸环化酶，利钠肽受体2（NPR 2），是环磷酸鸟苷（cGMP）稳态的关键调节剂。CNP-NPR 2-cGMP信号级联在卵母细胞减数分裂的进展中起重要作用，这对于雌性哺乳动物的生育力是必需的。在排卵前卵泡中，促黄体生成素（LH）诱导的CNP及其编码的信使RNA（mRNA）利钠肽前体C（Nppc）的减少是卵母细胞减数分裂恢复的先决条件。然而，从未确定LH如何降低CNP/Nppc。在本研究中，我们确定tristetraprolin（TTP），也称为锌指蛋白36（ZFP 36），一种普遍表达的mRNA不稳定蛋白，是LH诱导的Nppc mRNA减少的关键机制。Zfp 36 mRNA在壁颗粒细胞（MGCs）中瞬时上调，以响应LH峰。功能丧失和获得分析表明，TTP是排卵前MGCs中Nppc mRNA降解所必需的，其靶向是Nppc 3′ UTR中罕见的非典型富含AU的元件。此外，MGC特异性敲除Zfp 36，以及慢病毒介导的敲除在体内，削弱LH/hCG诱导的Nppc mRNA的下降和卵母细胞减数分裂的恢复。此外，我们发现LH/hCG通过EGFR-ERK 1/2依赖性途径激活Zfp 36/TTP表达。我们的研究结果揭示了TTP诱导的mRNA降解，一个全球性的转录后调节机制，在协调卵母细胞减数分裂的进展的功能作用。我们还提供了一个机制，了解CNP依赖的cGMP稳态在不同的细胞过程。

Significance The fertility of female mammals depends upon the well-orchestrated progression of oocyte meiosis, the female germ cell division that is essential for haploid oocyte formation. In preovulatory follicles, how LH induces a decrease in CNP and its encoding mRNA Nppc, a prerequisite for oocyte meiotic resumption, remains an outstanding question to understand the mechanism that controls oocyte meiosis. The present study shows that TTP, an mRNA-destabilizing protein, is one of the regulatory components responsible for the LH-induced rapid decrease in Nppc mRNA and oocyte meiotic resumption. This finding not only highlights the importance of posttranscriptional regulation in the follicle periphery to fine-tune oocyte meiosis but also provides an insight into CNP-dependent cGMP homeostasis in other physiological systems. 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.

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

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