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: 10682324
• 负责人: Karen A Schindler
• 金额: $ 6.14万
• 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/10682324
• 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.

项目摘要 减数分裂是对有性繁殖必不可少的细胞分裂过程，因为它会产生单倍配子 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一无二的 染色单体保持彼此附着，而同源染色体对分离。在人类中 MI中发生的错误在女配子（卵母细胞）的高度很高，导致不育症，流产或出生 缺陷，但是控制MI的分子机制知之甚少。在我们的实验室工作 发挥了解剖用于控制MI来解释这种现象的信号传导机制。 Aurora蛋白激酶家族由三个成员组成：Aurka，Aurkb和Aurkc。奥克斯 是有丝分裂中染色体隔离的必要调节剂，并且需要完成它们的活动才能完成 MI染色体分离。 Aurkc的表达仅限于配子，并且在某些人中被异常表达 癌症。但是，由于Aurkc与Aurkb标准方法共享高序列同源 了解他们的MI特异性功能是不够的。我们在创建和评估卵母细胞方面的专业知识 - 特定的Aurk淘汰小鼠使我们能够揭示为什么卵母细胞包含两个的奥秘 彼此相似的激酶。我们不仅确定了Aurkb和Aurkc函数 彼此不同，我们发现这三个Aurks相互调节。在这个建议中，我们 旨在继续在MI期间剖析每个Aurk的要求，并确定如何以及为什么 Aurks互相调节。通过研究所有三个Aurk家族成员的功能，我们将发现 进化益处和表达三个极光的后果。为此，我们将：1）阐明如何 Aurka和Aurkc的反作用活动需要建立MI纺锤体，2）检查细胞系 异常表达Aurkc以确定这些反作用活动是否在有丝分裂中驱动非整倍性，而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有助于我们充分了解这些激酶在MI期间的运作方式 强调了如何控制有丝分裂和MI之间的明显差异。重要的是，这些数据将删除 关于如何控制卵母细胞的MI染色体分离的启发以及为什么女性通常会出现问题 导致非整倍性。