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: 10457384
• 负责人: Karen A Schindler
• 金额: $ 38.75万
• 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/10457384
• 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 减数分裂是细胞分裂的过程，这是必不可少的有性生殖，因为它创造了单倍体配子 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，因为复制的姊妹染色体在减数分裂I（MI）期间的染色体分离是独特的。 染色单体保持彼此附着，而同源染色体对分离。在人类中， MI错误在女性配子（卵母细胞）中发生率极高，导致不孕、流产或出生 缺陷，但控制MI的分子机制知之甚少。我们实验室的工作 有助于解剖用于控制MI的信号机制，以解释这种现象。 Aurora蛋白激酶家族由三个成员组成：AURKA、AURKB和AURKC。关于AURK 是有丝分裂中染色体分离的重要调节因子，它们的活性是完成 MI染色体分离。AURKC的表达仅限于配子，并且在某些细胞中异常表达。 癌的然而，由于AURKC与AURKB具有高度的序列同源性，因此， 了解他们的MI特定功能是不够的。我们在创造和评估卵母细胞方面的专业知识- 特异性的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 彼此相似的激酶。我们不仅确定了AURKB和AURKC函数 我们发现，这三种AURK相互独立，相互调节。在本提案中，我们 我的目标是在MI期间继续剖析每个AURK的要求，并确定如何以及为什么 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 进化的好处和表达三个AURK的后果。要做到这一点，我们将：1）阐明如何 AURKA和AURKC的反作用活性是构建MI纺锤体所必需的，2）检查 异常表达AURKC以确定这些反作用活性是否在有丝分裂中驱动非整倍性，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MI期间如何运作， 突出了有丝分裂和MI控制方式之间的明显差异。重要的是，这些数据将 关于MI染色体分离在卵母细胞中是如何控制的以及为什么它在女性中通常会出错 导致非整倍性。