TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa
TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa
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TCTE1 是动力蛋白调节复合物的保守成分，是小鼠精子运动和代谢所必需的
DOI：
10.1073/pnas.1621279114
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发表时间：
2017-07-03
影响因子：
11.1
通讯作者：
Liu, Mingxi
中科院分区：
文献类型：
--
作者：
Castaneda, Julio M.;Hua, Rong;Liu, Mingxi
不孕不育是一个全球性的问题，困扰着15%的夫妇，在50%的情况下，归因因素与男性有关。在这些不育男性中，18%的人表现出精子活动力下降（弱精子症）。精子的运动能力取决于鞭毛的形成和功能，鞭毛是一种用于运动的修饰的纤毛。纤毛几乎存在于脊椎动物的每个细胞中，并且对于正常器官功能至关重要。纤毛形成缺陷导致严重的综合征疾病，称为纤毛病，影响许多组织（例如，多囊肾疾病），其中男性不育症通常是共病的。小鼠遗传学的进展涉及几个基因负责在人类中观察到的纤毛病变。在这里，我们确定了一个非综合征鞭毛蛋白，TCTE 1，这是所需的小鼠精子活力。鞭毛和纤毛是重要的细胞器，它们为细胞提供了感知和通过其环境的手段。鞭毛和纤毛的中心组成部分是轴丝，它包括“9+2”微管排列、动力蛋白臂、放射状辐条和连接蛋白-动力蛋白调节复合物（N-DRC）。轴丝组件不能正确组装导致鞭毛缺陷，在人类中导致一系列被称为纤毛病的疾病。纤毛病可以表现为严重的综合征疾病，影响肺和肾功能，中枢神经系统发育，骨形成，内脏器官组织和生殖。T-Complex-Associated-Testis-Expressed 1（TCTE 1）是一种进化上保守的轴丝蛋白，从衣原体（DRC 5）到哺乳动物存在，定位于N-DRC。在这里，我们表明，小鼠TCTE 1是睾丸丰富的表达，其mRNA出现在早期圆形精子细胞和蛋白定位于鞭毛。TCTE 1长498个氨基酸，在C末端具有富含亮氨酸的重复结构域，并且存在于含有鞭毛的真核生物中。Tcte 1基因敲除导致雄性不育，因为Tcte 1缺失的精子显示异常的运动力。虽然Tcte 1突变精子的轴丝结构正常，但Tcte 1缺失精子的ATP显著减少，ATP被动力蛋白马达用于产生鞭毛的弯曲力。这些数据提供了一个链接，以确定轴丝功能，精子活力和男性生育力所需的分子复杂性。
Significance Infertility is a global problem that afflicts 15% of couples, and in 50% of cases, the attributing factor is linked to men. Among these infertile men, 18% specifically exhibit decreased motility of sperm (asthenozoospermia). Sperm motility is dependent on the formation and functioning of the flagellum, a modified cilium used for locomotion. Cilia are present in almost every cell of vertebrates and are essential for proper organ functioning. Defects in cilia formation lead to severe syndromic diseases, termed ciliopathies, affecting numerous tissues (e.g., polycystic kidney disease), wherein male infertility is often comorbid. Advances in mouse genetics implicate several genes responsible for ciliopathies observed in humans. Here, we identify a nonsyndromic flagellum protein, TCTE1, that is required for sperm motility in mice. Flagella and cilia are critical cellular organelles that provide a means for cells to sense and progress through their environment. The central component of flagella and cilia is the axoneme, which comprises the “9+2” microtubule arrangement, dynein arms, radial spokes, and the nexin-dynein regulatory complex (N-DRC). Failure to properly assemble components of the axoneme leads to defective flagella and in humans leads to a collection of diseases referred to as ciliopathies. Ciliopathies can manifest as severe syndromic diseases that affect lung and kidney function, central nervous system development, bone formation, visceral organ organization, and reproduction. T-Complex-Associated–Testis-Expressed 1 (TCTE1) is an evolutionarily conserved axonemal protein present from Chlamydomonas (DRC5) to mammals that localizes to the N-DRC. Here, we show that mouse TCTE1 is testis-enriched in its expression, with its mRNA appearing in early round spermatids and protein localized to the flagellum. TCTE1 is 498 aa in length with a leucine rich repeat domain at the C terminus and is present in eukaryotes containing a flagellum. Knockout of Tcte1 results in male sterility because Tcte1-null spermatozoa show aberrant motility. Although the axoneme is structurally normal in Tcte1 mutant spermatozoa, Tcte1-null sperm demonstrate a significant decrease of ATP, which is used by dynein motors to generate the bending force of the flagellum. These data provide a link to defining the molecular intricacies required for axoneme function, sperm motility, and male fertility.