SAK/PLK4 is required for centriole duplication and flagella development
SAK/PLK4 is required for centriole duplication and flagella development
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DOI：
10.1016/j.cub.2005.11.042
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发表时间：
2005-12-20
期刊：
影响因子：
9.2
通讯作者：
Glover, DM
中科院分区：
文献类型：
--
作者：
Bettencourt-Dias, M;Rodrigues-Martins, A;Glover, DM
背景：SAK/PLK4是polo样激酶家族的一个独特成员。SAK（-/-）小鼠在胚胎发生过程中死亡，而SAK（+/-）小鼠发生肝脏和肺部肿瘤，SAK(+/-) mef显示有丝分裂异常。然而，这些表型背后的机制尚不清楚。结果：在这里，我们发现果蝇细胞中SAK的下调，通过突变或RNAi，导致中心体核心结构中心粒的丢失。这样的细胞能够经历反复的细胞分裂，但显示出广泛的无组织的有丝分裂纺锤杆。我们还发现SAK突变体在雄性减数分裂前的有丝分裂中失去中心粒，但仍然产生16个初级精母细胞的囊泡，与野生型一样。精子发生过程中定型细胞分裂的数学模型可以解释这种由中心粒复制缺陷造成的损失。SAK突变体的大多数精子缺乏中心粒，因此不能产生精子轴突。最后，我们发现人类细胞中SAK的消耗也会阻止中心粒复制并引起有丝分裂异常。结论：SAK/PLK4在果蝇和人类细胞中都是中心粒复制所必需的。果蝇细胞可以忍受中心粒的缺乏并进行有丝分裂，但不能形成基体，因此不能形成鞭毛。缺乏SAK的人类细胞表现出易出错的有丝分裂，可能是其肿瘤抑制作用的基础。
Background: SAK/PLK4 is a distinct member of the polo-like kinase family. SAK(-/-) mice die during embryogenesis, whereas SAK(+/-) mice develop liver and lung tumors and SAK(+/-) MEFs show mitotic abnormalities. However, the mechanism underlying these phenotypes is still not known.Results: Here, we show that downregulation of SAK in Drosophila cells, by mutation or RNAi, leads to loss of centrioles, the core structures of centrosomes. Such cells are able to undergo repeated rounds of cell division, but display broad disorganized mitotic spindle poles. We also show that SAK mutants lose their centrioles during the mitotic divisions preceding male meiosis but still produce cysts of 16 primary spermatocytes as in the wild-type. Mathematical modeling of the stereotyped cell divisions of spermatogenesis can account for such loss by defective centriole duplication. The majority of spermatids in SAK mutants lack centrioles and so are unable to make sperm axonemes. Finally, we show that depletion of SAK in human cells also prevents centriole duplication and gives rise to mitotic abnormalities.Conclusions: SAK/PLK4 is necessary for centriole duplication both in Drosophila and human cells. Drosophila cells tolerate the lack of centrioles and undertake mitosis but cannot form basal bodies and hence flagella. Human cells depleted of SAK show error-prone mitosis, likely to underlie its tumor-suppressor role.