Zheng Ping, Dean Jurrien
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7473-8. doi: 10.1073/pnas.0900519106. Epub 2009 Apr 17.
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.
在卵子发生过程中，哺乳动物的卵子会积累早期胚胎发育所需的蛋白质。尽管有限的数据表明这些母体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，但它们在着床前发育中的全部功能仍 largely 未知。在这里，我们报告了母体蛋白质在维持早期卵裂小鼠胚胎发育中染色体稳定性和整倍性方面的作用。Filia 在生长中的卵母细胞中表达，编码一种与 MATER 结合的蛋白质，并参与皮质下母体复合体，这对卵裂期胚胎发育至关重要。Filia 母体储存的耗尽会损害着床前胚胎发育，导致非整倍体发生率很高，这是由异常纺锤体组装、染色体排列错误和纺锤体组装检查点（SAC）失活引起的。在帮助确保正常纺锤体形态发生方面，Filia 通过 RhoA 信号通路调节关键纺锤体组装调节因子（即 AURKA、PLK1 和γ-微管蛋白）向微管组织中心的正确分配。同时，Filia 是将 SAC 的重要组成部分 MAD2 定位到动粒以实现 SAC 功能所必需的。因此，Filia 对于整合调节因子的时空定位至关重要，这有助于确保着床前小鼠发育中的整倍性和高质量细胞周期进程。高度保守的人类同源物中的缺陷可能起类似作用，并解释人类反复发生的胎儿流产。
