1月27日，由國際著名專業(yè)學(xué)術(shù)期刊《癌基因》（Oncogne）創(chuàng)刊人,，原主編Prem Reddy教授主編，美國SAGE出版集團(tuán)出版發(fā)行的專業(yè)學(xué)術(shù)月刊《基因與癌癥》（Genes & Cancer）正式上網(wǎng)發(fā)行，這本新創(chuàng)刊的雜志以封面文章的形式發(fā)表了由上海交通大學(xué)醫(yī)學(xué)院王鑄鋼教授課題組的一項最新研究成果：“手術(shù)切除”Kif18a基因使雄性實驗鼠不育,、睪丸萎縮、精子缺失,！從而在國際上首次利用哺乳動物模型證實Kif18a基因突變與精子發(fā)生發(fā)育之間的因果關(guān)系,。這項研究成果不僅有助于闡明人類精子發(fā)生發(fā)育中的一些重要理論問題，而且對男性生殖健康、不育癥治療和男性計劃生育技術(shù)的研究和開發(fā)具有重要理論和實際意義,。
課題組聯(lián)合國內(nèi)外合作伙伴,，采用多種技術(shù)手段全方位揭示出Kif18a，驅(qū)動蛋白超家族中的一個新成員,，在精子發(fā)生發(fā)育過程中不可或缺的重要作用,。紡錘體是細(xì)胞分裂過程中形成的重要細(xì)胞器,，在細(xì)胞分裂后期染色體的分離過程中具有重要作用,。實驗證明Kif18a功能缺失直接造成細(xì)胞分裂過程中紡錘體形成障礙、紡錘絲微管分布及動態(tài)紊亂,、染色體集合異常且不能均等分離,，最終導(dǎo)致細(xì)胞死亡。進(jìn)一步研究發(fā)現(xiàn)Kif18a在細(xì)胞分裂過程中可以結(jié)合紡錘體檢查點蛋白BubR1和Cenp-E,，穩(wěn)定后兩者蛋白水平，參與其功能調(diào)節(jié),，為細(xì)胞分裂提供所需動力并維持紡錘體結(jié)構(gòu)和功能正常,，使細(xì)胞分裂能順利完成,。
值得一提的是,，近年來由于環(huán)境及社會因素的變化，男性生殖健康的問題日趨嚴(yán)重,。不僅精子的數(shù)量在逐年減少，而且精子的質(zhì)量也在逐年下降,，由此帶來男性不育癥發(fā)生率的逐年上升,。據(jù)統(tǒng)計，因各種原因?qū)е虏挥姆驄D約占育齡夫婦的15%,，其中,，男性因素約占一半。雖然導(dǎo)致男性不育癥的病因有多種多樣,，但仍然有約一半的患者病因不明,。Kif18a基因功能的發(fā)現(xiàn)無疑為男性不育癥病因研究開辟了新的方向，未來將有可能為男性不育癥病因診斷,、治療及男性節(jié)育新技術(shù)的發(fā)展帶來希望。
該項目研究成果是由上海交通大學(xué)醫(yī)學(xué)院及其附屬瑞金醫(yī)院,、美國紐約大學(xué)醫(yī)學(xué)院,、中科院健康科學(xué)研究所、上海南方模式生物研究中心等單位的十余位科研人員經(jīng)過近5年的協(xié)作攻關(guān)完成的,。期間,，先后獲得了國家自然科學(xué)基金重點項目、國家“十一五”科技支撐計劃重點項目,、上海市科委研究項目,、上海市教委E-研究院項目的資助。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
