Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo
Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo
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DOI：
10.1073/pnas.1400568111
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发表时间：
2014-04-15
影响因子：
11.1
通讯作者：
Anderson, Kathryn V.
中科院分区：
文献类型：
--
作者：
Bazzi, Hisham;Anderson, Kathryn V.
中心体是动物细胞的微管组织中心，组织间期微管和有丝分裂纺锤体。中心粒是组织中心体的基于微管的结构，中心粒生物发生需要一组确定的蛋白质，包括纺锤体组装缺陷 4 (SAS4) (CPAP/CENPJ)。中心粒和中心体的生物学功能因动物而异，哺乳动物中心体的功能尚未在遗传学上得到定义。在这里，我们使用小鼠 Sas4 的无效突变来定义哺乳动物中心粒体内的细胞和发育功能。 Sas4缺失的胚胎缺乏中心体，但可以存活到妊娠中期。正如预期的那样，Sas(4-/-) 突变体缺乏初级纤毛，因此无法对 Hedgehog 信号做出反应，但其他发育信号通路在突变体中是正常的。与缺乏纤毛的突变体不同，Sas(4-/-) 胚胎表现出与 p53 整体表达升高相关的广泛细胞凋亡。 Sas(4-/-) p53(-/-) 双突变体胚胎中的细胞死亡得以挽救，这表明哺乳动物中心粒可防止 p53 依赖性细胞凋亡途径的激活。双极纺锤体组织、染色体分离、细胞周期特征或DNA损伤反应的异常不会激活p53的表达，而这些在Sas(4-/-)突变体中是正常的。相反，实时成像显示，当两个无心粒纺锤体极组装时，突变体的前中期持续时间延长。独立实验表明，延长纺锤体组装足以触发 p53 依赖性细胞凋亡。我们得出的结论是，由于中心粒缺失而导致的前中期短暂延迟会激活小鼠胚胎快速分裂细胞中先前未描述的 p53 依赖性细胞死亡途径。
Centrosomes are the microtubule-organizing centers of animal cells that organize interphase microtubules and mitotic spindles. Centrioles are the microtubule-based structures that organize centrosomes, and a defined set of proteins, including spindle assembly defective-4 (SAS4) (CPAP/CENPJ), is required for centriole biogenesis. The biological functions of centrioles and centrosomes vary among animals, and the functions of mammalian centrosomes have not been genetically defined. Here we use a null mutation in mouse Sas4 to define the cellular and developmental functions of mammalian centrioles in vivo. Sas4-null embryos lack centrosomes but survive until midgestation. As expected, Sas(4-/-) mutants lack primary cilia and therefore cannot respond to Hedgehog signals, but other developmental signaling pathways are normal in the mutants. Unlike mutants that lack cilia, Sas(4-/-) embryos show widespread apoptosis associated with global elevated expression of p53. Cell death is rescued in Sas(4-/-) p53(-/-) double-mutant embryos, demonstrating that mammalian centrioles prevent activation of a p53-dependent apoptotic pathway. Expression of p53 is not activated by abnormalities in bipolar spindle organization, chromosome segregation, cell-cycle profile, or DNA damage response, which are normal in Sas(4-/-) mutants. Instead, live imaging shows that the duration of prometaphase is prolonged in the mutants while two acentriolar spindle poles are assembled. Independent experiments show that prolonging spindle assembly is sufficient to trigger p53-dependent apoptosis. We conclude that a short delay in the prometaphase caused by the absence of centrioles activates a previously undescribed p53-dependent cell death pathway in the rapidly dividing cells of the mouse embryo.