Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis

项目摘要 减数分裂是有性繁殖所必需的细胞分裂过程，因为它产生单倍体配子。 来自二倍体前体细胞。减数分裂I(MI)期间的染色体分离是独特的，因为复制的姐妹 当同源染色体对分离时，染色单体保持彼此连接。在人类身上， MI的错误发生在女性配子(卵母细胞)中的比例高得惊人，导致不孕、流产或出生。 然而，控制心肌梗死的分子机制却知之甚少。我们实验室的工作一直是 有助于剖析用于控制心肌梗死的信号机制，以解释这一现象。 Aurora蛋白激酶家族由三个成员组成：AURKA、AURKB和AURKC。奥里克一家 是有丝分裂中染色体分离的重要调节因子，它们的活动是完成 小鼠染色体分离。AURKC的表达仅限于配子，在一些 癌症。然而，因为AURKC与AURKB有很高的序列同源性，所以标准方法 了解他们特定于MI的功能是不够的。我们在创造和评估卵母细胞方面的专业知识- 特定的AURK基因敲除小鼠使我们有能力解开为什么卵母细胞含有两个 彼此相似的蛋白激酶。我们不仅确定了AURKB和AURKC函数 不同的是，我们发现这三个AURK是相互制约的。在这项提案中，我们 目的是继续分析MI期间每个AURK的需求，并确定如何以及为什么 AURK相互监管。通过研究AURK家族所有三个成员的功能，我们将揭示 进化利益和表达三个AURK的后果。为此，我们将：1)阐明如何 AURKA和AURKC的反作用活动是建立MI纺锤体所必需的，2)检查细胞系 异常表达AURKC以确定这些反作用活动是否导致有丝分裂中的非整倍体，以及3) 确定AURKB如何调节MI期间主轴组件检查点所需的蛋白质。 从我们的研究中获得的信息将帮助我们充分了解这些激酶在心肌梗死期间是如何运作的 突出了有丝分裂和心肌梗死如何控制之间的明显差异。重要的是，这些数据将 MI染色体分离是如何在卵母细胞中被控制的，以及为什么它在女性中经常出错 导致非整倍体。

Project Summary Meiosis is the cell division process that is essential for sexual reproduction because it creates haploid gametes from diploid precursor cells. Chromosome segregation during meiosis I (MI) is unique because replicated sister chromatids remain attached to one another while homologous chromosome pairs segregate. In humans, mistakes in MI occur are strikingly high in female gametes (oocytes), resulting in infertility, miscarriage, or birth defects, yet the molecular mechanisms that control MI are poorly understood. Work in our lab has been instrumental in dissecting the signaling mechanisms used to control MI to explain this phenomenon. The Aurora protein kinase family is comprised of three members: AURKA, AURKB and AURKC. The AURKs are essential regulators of chromosome segregation in mitosis, and their activities are required for completing MI chromosome segregation. AURKC expression is limited to gametes and is aberrantly expressed in some cancers. Yet, because AURKC shares high sequence homology with AURKB standard approaches to understand their MI-specific functions were not sufficient. Our expertise in creating and evaluating oocyte- specific AURK knockout mice has afforded us the ability to unravel the mystery of why oocytes contain two kinases that are similar to one another. Not only have we identified AURKB and AURKC functions that are distinct from one another, we have discovered that the three AURKs regulate one another. In this proposal, we aim to continue to dissect the requirements for each AURK during MI, and to determine how and why the AURKs regulate one another. By studying the functions of all three AURK family members, we will uncover the evolutionary benefit and the consequences of expressing three AURKs. To do so we will: 1) Elucidate how AURKA and AURKC counter-acting activities are required to build an MI spindle, 2) examine cell lines that aberrantly express AURKC to determine if these counter-acting activities drive aneuploidy in mitosis, and 3) determine how AURKB regulates proteins required for the spindle assembly checkpoint during MI. Information gained from our studies will help us fully understand how these kinases operate during MI while highlighting distinct differences between how mitosis and MI are controlled. Importantly, these data will shed light on how MI chromosome segregation is controlled in oocytes and why it commonly goes awry in women leading to aneuploidy.