Loss of DRC1 function leads to multiple morphological abnormalities of the sperm flagella and male infertility in human and mouse.
Loss of DRC1 function leads to multiple morphological abnormalities of the sperm flagella and male infertility in human and mouse.
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DRC1功能丧失会导致人类和小鼠精子鞭毛的多种形态异常以及男性不育
DOI：
10.1093/hmg/ddab171
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发表时间：
2021-10-13
影响因子：
3.5
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Zhang J;He X;Wu H;Zhang X;Yang S;Liu C;Liu S;Hua R;Zhou S;Zhao S;Hu F;Zhang J;Liu W;Cheng H;Gao Y;Zhang F;Cao Y;Liu M
运动纤毛和鞭毛缺陷可导致原发性纤毛运动障碍，这是一种多系统遗传性疾病，影响约1：10 000的个体。连接蛋白-动力蛋白调节复合物（N-DRC）连接鞭毛内相邻的双微管，作为衣原体运动的中心调节枢纽。在此，我们在人类患者中发现了两种与精子鞭毛（MMAF）的多种形态异常和男性不育相关的同源DRC1变异体。C57 BL/6背景的Drc1 −/−、Drc1R554X/R554X和Drc1W244X/W244X小鼠在青春期前死亡。然而，当引入ICR背景时，其中一些小鼠能够存活并重现在人类患者中检测到的MMAF表型。通过分析这些动物，我们确定DRC1是纤毛和鞭毛中N-DRC组装的重要调节因子。当DRC1缺失时，这会导致纤毛缩短，从而损害其运动性。与精子鞭毛中DRC1缺陷相关的损伤比纤毛中的损伤更明显，除了DRC结构的丧失外，还表现为完全轴丝结构紊乱。总而言之，这些发现表明，DRC1是鞭毛而不是纤毛的结构稳定性所必需的，强调了这种蛋白质在哺乳动物物种中的关键作用。
Motile cilia and flagellar defects can result in primary ciliary dyskinesia, which is a multisystemic genetic disorder that affects roughly 1:10 000 individuals. The nexin-dynein regulatory complex (N-DRC) links neighboring doublet microtubules within flagella, serving as a central regulatory hub for motility in Chlamydomonas. Herein, we identified two homozygousDRC1variants in human patients that were associated with multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility.Drc1−/−,Drc1R554X/R554XandDrc1W244X/W244Xmice on the C57BL/6 background suffered from pre-pubertal mortality. However, when the ICR background was introduced, some of these mice were able to survive and recapitulate the MMAF phenotypes detected in human patients. By analyzing these animals, we determined that DRC1 is an essential regulator of N-DRC assembly in cilia and flagella. When DRC1 is absent, this results in the shortening of cilia and consequent impairment of their motility. Damage associated with DRC1 deficiency in sperm flagella was more pronounced than in cilia, as manifested by complete axoneme structural disorder in addition to the loss of the DRC structure. Altogether, these findings suggest that DRC1 is required for the structural stability of flagella but not cilia, emphasizing the key role of this protein in mammalian species.
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影响因子：
4.5
作者：
Fanourgakis G;Lesche M;Akpinar M;Dahl A;Jessberger R
通讯作者：
Jessberger R
影响因子：
4.8
作者：
Lin, Jianfeng;Tritschler, Douglas;Nicastro, Daniela
通讯作者：
Nicastro, Daniela
影响因子：
16.8
作者：
Gui M;Ma M;Sze-Tu E;Wang X;Koh F;Zhong ED;Berger B;Davis JH;Dutcher SK;Zhang R;Brown A
通讯作者：
Brown A
DOI：
10.1073/pnas.1910960116
发表时间：
2019-11-12
影响因子：
11.1
作者：
Gui, Long;Song, Kangkang;Nicastro, Daniela
通讯作者：
Nicastro, Daniela
影响因子：
3.5
作者：
Li, Weiyu;He, Xiaojin;Cao, Yunxia
通讯作者：
Cao, Yunxia