Role of Filia, a maternal effect gene, in maintaining euploidy during cleavage-stage mouse embryogenesis
Role of Filia, a maternal effect gene, in maintaining euploidy during cleavage-stage mouse embryogenesis
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DOI：
10.1073/pnas.0900519106
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发表时间：
2009-05-05
影响因子：
11.1
通讯作者：
Dean, Jurrien
中科院分区：
文献类型：
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作者：
Zheng, Ping;Dean, Jurrien
在卵子发生过程中，哺乳动物的卵子积累了早期胚胎发生所需的蛋白质。尽管有限的数据表明这些母性因子在染色质重编程和胚胎基因组激活中起着至关重要的作用，但它们在植入前发育中的全部功能在很大程度上仍不清楚。在这里，我们报告了母体蛋白在小鼠早期卵裂胚胎发生中维持染色体稳定性和整倍体的作用。Filia在发育中的卵母细胞中表达，编码一种与物质结合的蛋白质，并参与皮质下母体复合体，对卵裂期胚胎发育至关重要。母体丝状物的耗尽损害了植入前胚胎的发育，非整倍体的发生率很高，这是由于纺锤体组装异常、染色体不对齐和纺锤体组装检查点(SAC)失活造成的。为了帮助确保正常的纺锤体形态发生，Filia通过RhoA信号通路调节关键的纺锤体组装调节器(即AURKA、PLK1和伽马微管蛋白)到微管组织中心的适当分配。同时，需要Filia将SAC的基本组件MAD2放置到动态芯片以启用SAC功能。因此，Filia是整合调控因子时空定位的核心，有助于确保着床前小鼠发育中的整倍体和高质量的细胞周期进展。保存完好的人类同源物中的缺陷可能起到类似的作用，并解释了反复出现的人类胎儿损耗。
During oogenesis, mammalian eggs accumulate proteins required for early embryogenesis. Although limited data suggest a vital role of these maternal factors in chromatin reprogramming and embryonic genome activation, the full range of their functions in preimplantation development remains largely unknown. Here we report a role for maternal proteins in maintaining chromosome stability and euploidy in early-cleavage mouse embryogenesis. Filia, expressed in growing oocytes, encodes a protein that binds to MATER and participates in a subcortical maternal complex essential for cleavage-stage embryogenesis. The depletion of maternal stores of Filia impairs preimplantation embryo development with a high incidence of aneuploidy that results from abnormal spindle assembly, chromosome misalignment, and spindle assembly checkpoint (SAC) inactivation. In helping to ensure normal spindle morphogenesis, Filia regulates the proper allocation of the key spindle assembly regulators (i.e., AURKA, PLK1, and gamma-tubulin) to the microtubule-organizing center via the RhoA signaling pathway. Concurrently, Filia is required for the placement of MAD2, an essential component of the SAC, to kinetochores to enable SAC function. Thus, Filia is central to integrating the spatiotemporal localization of regulators that helps ensure euploidy and high-quality cell cycle progression in preimplantation mouse development. Defects in the well-conserved human homologue could play a similar role and account for recurrent human fetal wastage.