mDia1/3 generate cortical F-actin meshwork in Sertoli cells that is continuous with contractile F-actin bundles and indispensable for spermatogenesis and male fertility.
mDia1/3 generate cortical F-actin meshwork in Sertoli cells that is continuous with contractile F-actin bundles and indispensable for spermatogenesis and male fertility.
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DOI：
10.1371/journal.pbio.2004874
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发表时间：
2018-09
期刊：
影响因子：
9.8
通讯作者：
Narumiya S
中科院分区：
文献类型：
--
作者：
Sakamoto S;Thumkeo D;Ohta H;Zhang Z;Huang S;Kanchanawong P;Fuu T;Watanabe S;Shimada K;Fujihara Y;Yoshida S;Ikawa M;Watanabe N;Saitou M;Narumiya S
形成蛋白是两类主要的肌动蛋白结合蛋白之一，具有成核和聚合活性。然而，尽管在我们的理解，其生化活性的进步，是否以及如何形成特定的肌动蛋白细胞骨架和功能在体内的生理背景下仍然很大程度上是模糊的。也不知道由formin产生的肌动蛋白丝如何与细胞中的其他ABP相互作用。在这里，我们结合联合收割机遗传操作的formins哺乳动物透明同系物1（mDia 1）和3（mDia 3）与超分辨率显微镜和单分子成像，并显示formins mDia 1和mDia 3主要表达在小鼠生精小管的支持细胞，并一起产生一个高度动态的皮质丝状肌动蛋白（F-肌动蛋白）网络，是连续的收缩肌动球蛋白束。mDia 1/3的丢失损害了这些F-肌动蛋白结构，诱导异位非收缩性espin 1-含有F-肌动蛋白束，破坏支持细胞-生殖细胞的相互作用，导致精子发生受损。这些结果共同证明了先前未被怀疑的mDia依赖的皮质F-肌动蛋白的调节机制，是哺乳动物精子发育和男性生育力不可或缺的。父亲的遗传信息通过精子传递给后代。精子独特的细胞形态在精子通过雌性生殖道的运输和与卵母细胞的受精中起着重要作用。支持细胞是位于睾丸生精小管中的体细胞，已知其有助于精子的发育。虽然许多研究已经分析了精子的发育，但其形态发生的机制仍然不清楚。在这项工作中，我们表明，发育中的精子和支持细胞之间的相互作用是精子形态发生的关键。我们进一步揭示，这种相互作用是强烈依赖于皮质F-肌动蛋白网络和收缩肌动球蛋白束的支持细胞，和两个肌动蛋白聚合和成核因子的肌动蛋白家族，mDia 1和mDia 3，参与了这两个肌动蛋白为基础的结构的产生。这些formins在小鼠中的丢失导致支持细胞肌动蛋白结构破坏，精子形态异常和男性不育。我们的结论是，mDia 1和mDia 3通过调节支持细胞的肌动蛋白细胞骨架结构在精子发育中发挥作用，这些蛋白质的缺陷可能导致男性不育。
Formin is one of the two major classes of actin binding proteins (ABPs) with nucleation and polymerization activity. However, despite advances in our understanding of its biochemical activity, whether and how formins generate specific architecture of the actin cytoskeleton and function in a physiological context in vivo remain largely obscure. It is also unknown how actin filaments generated by formins interact with other ABPs in the cell. Here, we combine genetic manipulation of formins mammalian diaphanous homolog1 (mDia1) and 3 (mDia3) with superresolution microscopy and single-molecule imaging, and show that the formins mDia1 and mDia3 are dominantly expressed in Sertoli cells of mouse seminiferous tubule and together generate a highly dynamic cortical filamentous actin (F-actin) meshwork that is continuous with the contractile actomyosin bundles. Loss of mDia1/3 impaired these F-actin architectures, induced ectopic noncontractile espin1-containing F-actin bundles, and disrupted Sertoli cell–germ cell interaction, resulting in impaired spermatogenesis. These results together demonstrate the previously unsuspected mDia-dependent regulatory mechanism of cortical F-actin that is indispensable for mammalian sperm development and male fertility. Paternal genetic information is transmitted to the offspring via sperm. The unique cell morphology of the sperm plays essential roles in sperm transport through the female reproductive tract and in fertilization with oocytes. Sertoli cells are somatic cells located in the seminiferous tubules of the testis and are known to contribute to the development of sperm. While many studies have analyzed sperm development, the mechanisms underlying its morphogenesis remain obscure. In this work, we showed that the interaction between developing sperm and Sertoli cells is critical for sperm morphogenesis. We further unraveled that this interaction is strongly dependent on the cortical F-actin meshwork and contractile actomyosin bundles of Sertoli cells, and that two actin polymerization and nucleation factors of the formin family, mDia1 and mDia3, are involved in the generation of both actin-based structures. Loss of these formins in mice result in disrupted Sertoli cell actin structures, abnormal sperm morphology, and male infertility. We conclude that mDia1 and mDia3 play a role in sperm development through the regulation of the actin cytoskeletal architecture of Sertoli cells and that defects in these proteins might contribute to male infertility.
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DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Hayashi S;Okada Y
通讯作者：
Okada Y
影响因子：
13.6
作者：
Fritzsche M;Erlenkämper C;Moeendarbary E;Charras G;Kruse K
通讯作者：
Kruse K
影响因子：
3.6
作者：
Goodson, Summer G.;Zhang, Zhaojun;O'Brien, Deborah A.
通讯作者：
O'Brien, Deborah A.
影响因子：
3.3
作者：
Chen, B;Li, AL;Bartles, JR
通讯作者：
Bartles, JR