A conserved requirement for Fbxo7 during male germ cell cytoplasmic remodelling
A conserved requirement for Fbxo7 during male germ cell cytoplasmic remodelling
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DOI：
10.1101/563718
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发表时间：
2019-02
期刊：
影响因子：
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通讯作者：
C. Rathje;S. Randle;Sarah Rawi;B. Skinner;Emma E. P. Johnson;Joanne Bacon;Myrto Vlazaki;N. Affara-N.-A
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作者：
C. Rathje;S. Randle;Sarah Rawi;B. Skinner;Emma E. P. Johnson;Joanne Bacon;Myrto Vlazaki;N. Affara-N.-A
Fbxo 7是SCF型泛素E3连接酶复合物的底物识别亚基。它在调节多种细胞类型如神经元、淋巴细胞和红细胞中的线粒体自噬、蛋白酶体活性和细胞周期方面具有重要的生理功能。在这里，我们表明，除了先前已知的帕金森病和造血表型，Fbxo 7缺陷的雄性小鼠是完全不育的。在这些男性中，尽管成功的减数分裂，核伸长和组蛋白从染色质中驱逐，发育中的精子细胞在精子发生后期被支持细胞吞噬，因为细胞经历细胞质重塑。令人惊讶的是，尽管所有生殖细胞的损失，有没有证据的共质体形成和细胞脱落，通常与精子细胞死亡在其他小鼠不育模型，这表明，新的细胞死亡和/或细胞处置机制可能参与Fbxo 7缺陷的男性。果蝇Fbxo 7的直系同源物，胡桃夹子（ntc）的突变先前显示在生殖细胞发育的类似阶段导致不育，表明对Fbxo 7的需求是保守的。ntc表型归因于通过与蛋白酶体调节剂DmPI 31相互作用的蛋白酶体误调节。我们的数据表明，而在小鼠中，对Fbxo 7的需求是独立的与PI 31的相互作用，或特别涉及到精子发生过程中的细胞质蛋白酶体活性。
Fbxo7 is the substrate-recognition subunit of an SCF-type ubiquitin E3 ligase complex. It has physiologically important functions in regulating mitophagy, proteasome activity and the cell cycle in multiple cell types, like neurons, lymphocytes and erythrocytes. Here we show that in addition to the previously-known Parkinsonian and haematopoietic phenotypes, Fbxo7-deficient male mice are completely sterile. In these males, despite successful meiosis, nuclear elongation and eviction of histones from chromatin, the developing spermatids are phagocytosed by Sertoli cells during late spermiogenesis, as the cells undergo cytoplasmic remodelling. Surprisingly, despite the loss of all germ cells, there was no evidence of the symplast formation and cell sloughing that is typically associated with spermatid death in other mouse sterility models, suggesting that novel cell death and/or cell disposal mechanisms may be engaged in Fbxo7-deficient males. Mutation of the Drosophila Fbxo7 orthologue, nutcracker (ntc) was previously shown to cause sterility at a similar stage of germ cell development, indicating that the requirement for Fbxo7 is conserved. The ntc phenotype was attributed to proteasome mis-regulation via an interaction with the proteasome regulator, DmPI31. Our data suggest rather that in mice, the requirement for Fbxo7 is either independent of its interaction with PI31, or relates specifically to cytoplasmic proteasome activity during spermiogenesis.