引言
在小鼠中,Intermitochondrial Cement(IMC)和拟染色质体(chromatoid body,CB)被定位为piRNA活性的中心位点,MIWI首先在IMC组装以加工piRNA,然后转运到CB进行功能部署。然而,支撑MIWI转移的监管机制仍然难以捉摸。
2024年3月15日,中国科学院分子细胞科学卓越创新中心/国科大杭州高等研究院刘默芳研究员、同济大学丁德强教授和国科大杭州高等研究院王鑫副研究员共同通讯在
Nature Communications
发表题为“
piRNA loading triggers MIWI translocation from the intermitochondrial cement to chromatoid body during mouse spermatogenesis”的研究论文,该研究揭示了piRNA加载是MIWI从IMC到CB易位的触发因素。
从机制上讲,piRNA加载通过削弱其与线粒体锚定的TDRKH的联系来促进 MIWI从IMC释放。这反过来又使MIWI的精氨酸甲基化成为可能,增强了其对TDRD6的结合亲和力并确保其在 CB 中的整合。值得注意的是,piRNA加载能力的丧失导致MIWI在IMC中捕获及其在雄性生殖细胞中的不稳定,导致小鼠精子发生缺陷和雄性不育。总的来说,该研究确立了piRNA在精子发生过程中MIWI易位中的关键作用,为哺乳动物的piRNA生物学提供了新的见解。
生殖颗粒(Germ granules)是主要存在于动物生殖细胞细胞质中的无膜细胞器,是各种RNA中心过程的组成部分。
虽然在动物生殖细胞中发现了大量具有不同成分和功能的生殖颗粒,Intermitochondrial Cement(IMC)和拟染色体(CB)是哺乳动物雄性生殖细胞中最广泛的特征。IMC可见为位于线粒体簇中的电子致密颗粒,首先出现在胎儿前精原细胞(prospermatogonia),在中粗线期精母细胞(mid-pachytene spermatocytes)中变得明显,然后随着线粒体弥散在晚粗线期精母细胞(late-pachytene spermatocytes)中逐渐解体,并在减数分裂后精子细胞阶段完全消失。
相比之下,CB前体细胞在晚粗线期精母细胞中以小颗粒的形式出现,位于靠近核包膜。
在减数分裂后的圆形精子细胞中,这些前体合并成CB,这是一种单生的、细丝状的、分叶状的核周颗粒。
值得注意的是,IMC和CB被假设分别作为哺乳动物雄性生殖细胞中 piRNA 加工和功能的平台。IMC 中 piRNA 加工蛋白的富集证实了这一观点,以及CB 中存在感受态 PIWI/piRNA 复合物。
尽管人们普遍认为IMC为CB提供前体材料,在 IMC 中产生的成熟 piRNA如何转变为CB中piRNA机制中的功能实体的机制基础仍然难以捉摸。
piRNA被认为与属于Argonaute家族PIWI分支的蛋白质合作,从而促进了它们的生物学作用,这对动物的生殖系发育至关重要。
PIWI/piRNA复合物的主要作用是沉默转座元件,从而保护种系基因组的完整性。然而,后来的研究已经证明了它们在蛋白质编码基因调控中的作用,扩大了对动物生殖细胞中PIWI/piRNA功能的理解。
在小鼠中,PIWI家族蛋白MIWI、MILI 和 MIWI2 在雄性生殖细胞中特异性表达,在精子发生过程中表现出时间和空间表达模式。
特别是,MIWI表达在粗线期精母细胞中起始,并通过减数分裂后的精子细胞持续存在。
先前的研究表明,MIWI最初通过与线粒体锚定的Tudor结构域蛋白TDRKH相互作用被募集到IMC,用于中粗线期精母细胞中的piRNA 加工。此后,MIWI在圆形精子细胞的CB中富集,在那里,MIWI与piRNA复合,发挥调节转座子和蛋白编码mRNA转录的功能。
尽管如此,在男性生殖细胞发育过程中,MIWI从产生piRNA的内乳细胞顺序易位到具有piRNA功能的CB的机制仍然是piRNA生物学的一个谜。
该研究阐明了piRNA负载在介导 MIWI 从 IMC到CB 的易位中的关键作用。
研究结果表明,piRNA负载促进了MIWI与TDRKH的脱离,促进了其从IMC的释放。值得注意的是,
这种分离使 MIWI 蛋白为精氨酸甲基化奠定了基础,随后通过其甲基化的精氨酸残基促进了其与TDRD6的结合,从而最终将其整合到CB中。
模式图(Credit:
Nature Communications)
通过产生piRNA加载缺陷的 Miwi突变小鼠,该研究证明了MIWI中piRNA 加载能力的丧失阻碍了其在精子发生过程中从 IMC 到 CB 的易位。
这种阻塞严重破坏了发育中的雄性生殖细胞中的MIWI稳定性,并导致小鼠的精子发生缺陷和雄性不育。
总的来说,该研究揭示了MIWI在发育中的雄性生殖细胞中连续易位的分子动力学,并在小鼠雄性生殖细胞分化过程中的piRNA加工和功能之间建立了机制桥梁。
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文章来源|“iNature”
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