Cnot3 is required for male germ cell development and spermatogonial stem cell maintenance.
Cnot3 is required for male germ cell development and spermatogonial stem cell maintenance.
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Cnot3 是雄性生殖细胞发育和精原干细胞维持所必需的。
DOI：
10.1101/2023.10.13.562256
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hu,Guang
中科院分区：
文献类型：
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作者：
Chen,Qing;Malki,Safia;Xu,Xiaojiang;Bennett,Brian;Lackford,BradL;Kirsanov,Oleksandr;Geyer,ChristopherB;Hu,Guang
精原干细胞(SSCs)是精子发生和终身生育的基础。SSCs进行不对称分裂，以补充它们的数量(自我更新)，或者产生在承诺分化之前增殖的未分化的祖细胞。然而，人们对管理SSC维护的监管机制知之甚少。在这里，我们证明了CCR4-NOT mRNA死烯基酶复合体CNOT3在维持小鼠精原细胞数量方面发挥着关键作用。CNOT3在未分化的精原细胞中高表达，精原细胞中CNOT3的缺失导致生殖细胞丢失和不育。单细胞分析表明，CNOT3缺失导致参与精原细胞分化的转录编码因子的下调，包括对SSC维持至关重要的谷胱甘肽氧化还原途径中的那些转录因子。综上所述，我们的研究表明，CNOT3-可能通过CCR4-非复合体-主动降解编码分化因子的转录本，以维持精原细胞池并确保精子发生的进展，突显了CCR4-非介导的转录后基因调控在男性生殖细胞发育中的重要性。
The foundation of spermatogenesis and lifelong fertility is provided by spermatogonial stem cells (SSCs). SSCs divide asymmetrically to either replenish their numbers (self-renewal) or produce undifferentiated progenitors that proliferate before committing to differentiation. However, regulatory mechanisms governing SSC maintenance are poorly understood. Here, we show that the CCR4-NOT mRNA deadenylase complex subunit CNOT3 plays a critical role in maintaining spermatogonial populations in mice. Cnot3 is highly expressed in undifferentiated spermatogonia, and its deletion in spermatogonia resulted in germ cell loss and infertility. Single cell analyses revealed that Cnot3 deletion led to the de-repression of transcripts encoding factors involved in spermatogonial differentiation, including those in the glutathione redox pathway that are critical for SSC maintenance. Together, our study reveals that CNOT3 – likely via the CCR4-NOT complex – actively degrades transcripts encoding differentiation factors to sustain the spermatogonial pool and ensure the progression of spermatogenesis, highlighting the importance of CCR4-NOT-mediated post-transcriptional gene regulation during male germ cell development.