2012年6月,BBA - Molecular and Cell Biology of Lipids杂志发表了中国科学院生物物理研究所苗龙课题组最新研究成果:Cholesterol and the biosynthesis of glycosphingolipids are required for sperm activation in Caenorhabditis elegans。该研究揭示出在精子活化早期,胆固醇与糖鞘脂形成的脂筏结构域参与了秀丽线虫精子细胞成熟的信号转导。
有性生殖的受精是一个复杂的分子事件。对于哺乳动物而言,进入雌性生殖道的精子细胞并不具备受精能力,必需在雌性生殖道内经过一段时间,发生生理与形态学的变化才能获得受精能力,这一过程被称之为精子获能。精子获能主要是精子细胞质膜蛋白发生多种分子变化和胆固醇的流失从而改变精子质膜的通透性与流动性,导致钙离子的流入,引起蛋白激酶的激活从而激活精子。
秀丽线虫是研究人类疾病分子机理的模式生物。与哺乳动物精子不同,线虫精子细胞以伪足的爬行取代鞭毛运动。然而,与高等动物的精子获能相似,线虫精子也需要一个精子活化的过程之后才具备受精能力。前期研究认为,由于线虫不具备胆固醇的生物合成途径,线虫的存活需摄入外源胆固醇;且胆固醇在线虫细胞中的含量极低,胆固醇被认为仅仅是其它信号分子的前体,而不是类似在高等动物中与糖鞘脂等在质膜上形成的脂筏结构域参与信号转导。
作者研究发现,胆固醇在线虫精子细胞质膜上高度富集。与高等动物的精子成熟类似,线虫的精子活化也伴随着质膜中胆固醇的流失。研究表明,细胞质膜中的胆固醇的存在对精子细胞的活化至关重要,揭示胆固醇在精子细胞质膜中可能形成脂筏微结构域参与精子细胞成熟过程中信号分子的筛选与信号转导。进一步研究发现,影响参与脂筏微结构域稳定性的其它标志物,如糖基化磷脂酰肌醇锚定蛋白或糖鞘脂,均可导致线虫精子细胞活化与细胞迁移运动异常。
生物物理所博士后窦江丽博士为本文第一作者。参与此工作的还有生物物理所的陈联万和博士生胡攸乔,苗龙博士是本文通讯作者。此项研究为科技部国家重点基础研究973计划和国家自然科学基金委员会资助。(生物谷Bioon.com)
doi:10.1016/j.bbalip.2012.03.005
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Cholesterol and the biosynthesis of glycosphingolipids are required for spermactivation in Caenorhabditiselegans
Jiangli Dou, Lianwan Chen, Youqiao Hu, Long Miao,
Ejaculated mammalian sperm must acquire fertilization capacity after residing into the female reproductive tract, a process collectively known as capacitation. Cholesterol efflux was required for sperm maturation. Different from flagellated sperm, C. eleganssperm are crawling cells. C. eleganssperm are highly enriched with cholesterol though this animal species lacks biosynthetic pathway for cholesterol and its survival requires an exogenous cholesterol supply. The low abundance of cholesterol in C. elegans lipid extract is thought insufficient to form lipid microdomains ubiquitously in this organism. We present evidence that cholesterol is enriched in the plasma membrane of C. elegans spermatids and that cholesterol- and glycosphingolipids (GSLs)-enriched membrane microdomains (lipid microdomains) mediate spermactivation. Disruption of sperm lipid microdomains by acute manipulation of cholesterol in vitro blocks the spermactivation. Restriction of cholesterol uptake also results in the abnormal spermactivation in both males and hermaphrodites. Manipulation of the integrity of lipid microdomains by targeting the biosynthesis of GSLs inhibits spermactivation and the inhibition can be rescued by the addition of exogenous GSLs. The cleavage of glycosylphosphatidylinositol (GPI)-anchored proteins, which are exclusively found in lipid microdomains, also affects spermactivation. We conclude that localized signaling mediated by lipid microdomains is critical for worm spermactivation. Lipid microdomains composed of cholesterol and GSLs have been observed in flagellated sperm of several animal species, thus cholesterol, before its efflux from the plasma membrane, might be needed to assemble into a platform for some more important upstream signal sorting during spermatogenesis than was previously thought.