中国科学院动物研究所李卫研究组的最新研究发现自噬(autophagy)作为重要的调节机制参与精子的分化与成熟,自噬的缺失会导致精子活力衰减,精子形态尤其是尾部结构遭到破坏,出现严重的畸形精子症。该项研究成果在线发表于6月17日Autophagy 杂志。

据国内精子库检测权威报告,我国正常成年男性精子合格率不足30%,WHO关于精子异常病人的鉴定标准也一直在更新,1987年正常形态精子的百分比为50%,而2010年第五版精液分析标准中,这一数值低至4%,引起广泛担忧。精子的分化与成熟需经历剧烈的形态与功能的变化,任何一步的差错都会直接导致精子分化发生异常,导致畸形精子症、弱精子症甚至无精子症。但是精子正常发育的保障机制目前所知甚少。李卫研究组的成果发现,精细胞中自噬被阻滞后,精子分化过程中一系列的关键结构的组装遭到破坏,如精子变形的支架-精子领(manchette)和保障精子运动的尾轴(axoneme),同时导致大量本该移除的胞质存留在精子头部,出现形态畸形与运动障碍。该研究进一步证明自噬过程通过特异的降解细胞骨架调节蛋白pDLIM1促进了细胞骨架的正常组装,保证了精子分化的正常进行。该研究不仅揭示了自噬在精子发育过程中的重要功能,同时提出了自噬对细胞骨架调节的关键环节,使精子形态建成的机制研究得到进一步完善。

李卫研究组博士生尚永亮为论文第一作者。该研究得到科技部重大基础研究计划(2012CB944404)、国家自然科学基金(31171374,31471277)等项目的资助。

动物所揭示自噬调节精子分化成熟的机制

原文摘要:

Autophagy regulates spermatid differentiation via degradation of pDLIM1

Spermiogenesis is a complex and highly ordered spermatid differentiation process that requires reorganization of cellular structures. We have previously found that Atg7 is required for acrosome biogenesis. Here, we show that autophagy regulates the round and elongating spermatids. Specifically, we found that Atg7 is required for spermatozoa flagella biogenesis and cytoplasm removal during spermiogenesis. Spermatozoa motility of atg7-null mice dropped significantly with some extra-cytoplasm retained on the mature sperm head. These defects are associated with an impairment of the cytoskeleton organization. Functional screening revealed that the negative cytoskeleton organization regulator, pDLIM1 (pDZ and LIM domain 1 [elfin]), needs to be degraded by the autophagy-lysosome-dependent pathway to facilitate the proper organization of the cytoskeleton. Our results thus provide a novel mechanism showing that autophagy regulates cytoskeleton organization mainly via degradation of pDLIM1 to facilitate the differentiation of spermatids.