Germinal Cell Aplasia in Kif18a Mutant Male Mice Due to Impaired Chromosome Congression and Dysregulated BubR1 and CENP-E.
Germinal Cell Aplasia in Kif18a Mutant Male Mice Due to Impaired Chromosome Congression and Dysregulated BubR1 and CENP-E.
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DOI：
10.1177/1947601909358184
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发表时间：
2010-01
期刊：
影响因子：
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通讯作者：
Wang ZG
中科院分区：
文献类型：
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作者：
Liu XS;Zhao XD;Wang X;Yao YX;Zhang LL;Shu RZ;Ren WH;Huang Y;Huang L;Gu MM;Kuang Y;Wang L;Lu SY;Chi J;Fen JS;Wang YF;Fei J;Dai W;Wang ZG
细胞分裂过程中染色体的不稳定性经常导致细胞死亡或恶性转化。在脊椎动物有丝分裂和减数分裂中，中期板上有序的染色体聚集是一个至关重要的过程，它受到包括运动蛋白在内的许多分子调节因子的控制。Kinesin-8 （Kif18A）通过负调控着丝粒振荡来控制中间区有丝分裂染色体的排列。在这里，作者报告说，破坏Kif18a功能会导致雄性小鼠完全不育，而雌性小鼠则不会。组织学检查显示，Kif18a−/−睾丸表现出严重的精管发育障碍。Kif18a−/−小鼠睾丸萎缩是由微管动力学和纺锤极完整性的扰动引起的，导致有丝分裂和减数分裂期间染色体聚集缺陷。在GC-1和HeLa细胞中，通过RNAi耗尽KIF18A会导致有丝分裂停滞，并伴有染色体不对齐和微管成核中心增加。由于微管动力学受到干扰，KIF18A的长期缺失导致细胞凋亡。进一步的研究表明，KIF18A沉默导致CENP-E和BubR1的降解，并伴有姐妹染色单体过早分离。KIF18A物理上与BubR1和CENP-E相互作用，这种相互作用在有丝分裂期间被调节。综上所述，这些研究表明，KIF18A对于细胞分裂过程中正常的染色体聚集是必不可少的，缺乏KIF18A功能会导致微管动力学、纺锤体完整性和检查点激活方面的严重缺陷，从而导致小鼠生发细胞发育不全。
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.