Germinal Cell Aplasia in Kif18a Mutant Male Mice Due to Impaired Chromosome Congression and Dysregulated BubR1 and CENP-E.
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.
Liu
Xue-Song
XS
Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
Zhao
Xu-Dong
XD
Wang
Xiaoxing
X
Yao
Yi-Xin
YX
Zhang
Liang-Liang
LL
Shu
Run-Zhe
RZ
Ren
Wei-Hua
WH
Huang
Ying
Y
Huang
Lei
L
Gu
Ming-Min
MM
Kuang
Ying
Y
Wang
Long
L
Lu
Shun-Yuan
SY
Chi
Jun
J
Fen
Jing-Sheng
JS
Wang
Yi-Fei
YF
Fei
Jian
J
Dai
Wei
W
Wang
Zhu-Gang
ZG