Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis

女性减数分裂过程中控制染色体分离的信号机制

• 批准号: 10581965
• 负责人: Karen A Schindler
• 金额: $ 11.91万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581965
• 关键词: Aneuploidy; Cell Division Process; Cell Line; Chromosome Pairing; Chromosome Segregation; Congenital Abnormality; Data; Diploidy; Family; Family member; Female; Germ Cells; Goals; Grant; Haploidy; Human; Infertility; Knockout Mice; Light; Malignant Neoplasms; Meiosis; Mitosis; Molecular; Oocytes; Phosphotransferases; Process; Protein Kinase; Proteins; Sequence Homology; Sexual Reproduction; Signal Transduction; Sister Chromatid; Spontaneous abortion; Woman; Work; aurora B kinase; aurora kinase A; egg; member; precursor cell; sperm cell

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.

项目概要 减数分裂是有性生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 染色单体保持彼此附着，而同源染色体对分离。在人类中， 女性配子（卵母细胞）中发生 MI 错误的比例惊人地高，导致不孕、流产或难产 缺陷，但控制 MI 的分子机制却知之甚少。我们实验室的工作已经 有助于剖析用于控制 MI 的信号机制以解释这种现象。 极光蛋白激酶家族由三个成员组成：AURKA、AURKB 和 AURKC。 AURKs 是有丝分裂中染色体分离的重要调节因子，它们的活动是完成有丝分裂所必需的 MI 染色体分离。 AURKC 表达仅限于配子，并且在某些配子中异常表达 癌症。然而，由于 AURKC 与 AURKB 标准方法具有高度的序列同源性 了解它们的 MI 特定功能还不够。我们在创建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能够解开为什么卵母细胞含有两个 彼此相似的激酶。我们不仅确定了 AURKB 和 AURKC 函数 我们发现这三个AURK 彼此不同，但它们相互调节。在这个提案中，我们 旨在继续剖析 MI 期间每个 AURK 的要求，并确定如何以及为何 AURK 相互调节。通过研究所有三个 AURK 家族成员的功能，我们将揭示 表达三个 AURK 的进化益处和后果。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会导致有丝分裂中的非整倍性，以及 3) 确定 AURKB 如何调节 MI 期间纺锤体组装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如何运作 强调了有丝分裂和 MI 控制方式之间的明显差异。重要的是，这些数据将会流失 了解卵母细胞中 MI 染色体分离的控制方式以及为何女性中这种现象通常会出现问题 导致非整倍体。