课题组联合国内外合作伙伴，采用多种技术手段全方位揭示出Kif18a，驱动蛋白超家族中的一个新成员，在精子发生发育过程中不可或缺的重要作用。纺锤体是细胞分裂过程中形成的重要细胞器，在细胞分裂后期染色体的分离过程中具有重要作用。实验证明Kif18a功能缺失直接造成细胞分裂过程中纺锤体形成障碍、纺锤丝微管分布及动态紊乱、染色体集合异常且不能均等分离，最终导致细胞死亡。进一步研究发现Kif18a在细胞分裂过程中可以结合纺锤体检查点蛋白BubR1和Cenp-E，稳定后两者蛋白水平，参与其功能调节，为细胞分裂提供所需动力并维持纺锤体结构和功能正常，使细胞分裂能顺利完成。
值得一提的是，近年来由于环境及社会因素的变化，男性生殖健康的问题日趋严重。不仅精子的数量在逐年减少，而且精子的质量也在逐年下降，由此带来男性不育症发生率的逐年上升。据统计，因各种原因导致不育的夫妇约占育龄夫妇的15%，其中，男性因素约占一半。虽然导致男性不育症的病因有多种多样，但仍然有约一半的患者病因不明。Kif18a基因功能的发现无疑为男性不育症病因研究开辟了新的方向，未来将有可能为男性不育症病因诊断、治疗及男性节育新技术的发展带来希望。
该项目研究成果是由上海交通大学医学院及其附属瑞金医院、美国纽约大学医学院、中科院健康科学研究所、上海南方模式生物研究中心等单位的十余位科研人员经过近5年的协作攻关完成的。期间，先后获得了国家自然科学基金重点项目、国家“十一五”科技支撑计划重点项目、上海市科委研究项目、上海市教委E-研究院项目的资助。（生物谷Bioon.com）
生物谷推荐原始出处：
Genes & Cancer vol. 1 no. 1 26-39 doi: 10.1177/1947601909358184
Germinal Cell Aplasia in Kif18a Mutant Male Mice Due to Impaired Chromosome Congression and Dysregulated BubR1 and CENP-E
Xue-song Liu1,*, Xu-dong Zhao2,*, Xiaoxing Wang3,*, Yi-xin Yao1,3, Liang-liang Zhang4, Run-zhe Shu4, Wei-hua Ren2, Ying Huang3, Lei Huang1, Ming-min Gu1, Ying Kuang2, Long Wang2,5, Shun-yuan Lu2,5, Jun Chi2, Jing-sheng Fen6, Yi-fei Wang6, Jian Fei2, Wei Dai3 and Zhu-Gang Wang1,2,4,5
1Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
2Shanghai Research Centre for Model Organisms, Shanghai, China
3Department of Environmental Medicine & Pharmacology, New York University School of Medicine, Tuxedo, NY, USA
4Laboratory of Genetic Engineering, Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTUSM, Shanghai, China
5State Key Laboratory of Medical Genomics, Rui-jin Hospital Affiliated with SJTUSM, Shanghai, China
6Department of Histology and Embryology, Faculty of Basic Medicine, SJTUSM, Shanghai, China
Chromosomal instability during cell division frequently causes cell death or malignant transformation. Orderly chromosome congression at the metaphase plate, a paramount process to vertebrate mitosis and meiosis, is controlled by a number of molecular regulators, including kinesins. Kinesin-8 (Kif18A) functions to control mitotic chromosome alignment at the mid-zone by negative regulation of kinetochore oscillation. Here the authors report that disrupting Kif18a function results in complete sterility in male but not in female mice. Histological examination reveals that Kif18a?/? testes exhibit severe developmental impairment of seminiferous tubules. Testis atrophy in Kif18a?/? mice is caused by perturbation of microtubule dynamics and spindle pole integrity, leading to chromosome congression defects during mitosis and meiosis. Depletion of KIF18A via RNAi causes mitotic arrest accompanied by unaligned chromosomes and increased microtubule nucleating centers in both GC-1 and HeLa cells. Prolonged depletion of KIF18A causes apoptosis due to perturbed microtubule dynamics. Further studies reveal that KIF18A silencing results in degradation of CENP-E and BubR1, which is accompanied by premature sister chromatid separation. KIF18A physically interacts with BubR1 and CENP-E, and this interaction is modulated during mitosis. Combined, the studies indicate that KIF18A is essential for normal chromosome congression during cell division and that the absence of KIF18A function causes severe defects in microtubule dynamics, spindle integrity, and checkpoint activation, leading to germinal cell aplasia in mice.
众说风云 (已有0条评论)
