【作者】 王铸钢；

【机构】 上海交大医学院上海南方模式生物研究中心；

【摘要】 <正>Orderly chromosome congression at the metaphase plate,paramount to vertebrate mitosis and meiosis,is controlled by a number of molecular regulators including kinesins.Kinesin-8 motor Kifl8a functions to control mitotic chromosome alignment at the midzone by negative control of kinetochore oscillation.Here we report that ablation of Kif18a function results in complete sterility in male but not in female mice.Histological examination reveals that Kifl 8a-/-testes exhibit severe developmental retardation of seminiferous tubules.Testis atrophy in Kifl 8a-/-mice is caused by perturbation of microtubule dynamics and spindle pole integrity,leading to compromised chromosome congression during mitosis and meiosis.Depletion of Kif18a via RNAi causes mitotic arrest accompanied by the presence of unaligned chromosomes at spindle pole regions 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 but not Aurora-B and Eg5.Intriguingly,BubR1 signals remain strong in unaligned kinetochores but not in mid-zone kinetochores although its level is also significantly reduced in Kif18a-depleted cells.Combined,our studies indicate that Kif18a is essential for normal chromosome congression during cell division and that absence of Kif18a function causes severe defects in microtubule dynamics and spindle integrity,leading to hypospermatogenesis in mice.更多还原

【Abstract】 Orderly chromosome congression at the metaphase plate,paramount to vertebrate mitosis and meiosis,is controlled by a number of molecular regulators including kinesins.Kinesin-8 motor Kifl8a functions to control mitotic chromosome alignment at the midzone by negative control of kinetochore oscillation.Here we report that ablation of Kif18a function results in complete sterility in male but not in female mice.Histological examination reveals that Kifl 8a-/-testes exhibit severe developmental retardation of seminiferous tubules.Testis atrophy in Kifl 8a-/-mice is caused by perturbation of microtubule dynamics and spindle pole integrity,leading to compromised chromosome congression during mitosis and meiosis.Depletion of Kif18a via RNAi causes mitotic arrest accompanied by the presence of unaligned chromosomes at spindle pole regions 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 but not Aurora-B and Eg5.Intriguingly,BubR1 signals remain strong in unaligned kinetochores but not in mid-zone kinetochores although its level is also significantly reduced in Kif18a-depleted cells.Combined,our studies indicate that Kif18a is essential for normal chromosome congression during cell division and that absence of Kif18a function causes severe defects in microtubule dynamics and spindle integrity,leading to hypospermatogenesis in mice.更多还原