Timing and regulation of meiotic commitment

减数分裂承诺的时间和调节

• 批准号: 9885436
• 负责人: Soni Lacefield
• 金额: $ 32.62万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885436
• 关键词: Address; Affect; Anaphase; Animal Model; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Centromere; Chromosome Segregation; Chromosomes; Closure by clamp; Data; Development; Developmental Disabilities; Diploid Cells; Down Syndrome; Edward' s syndrome; Engineering; Ensure; Failure; Genetic; Genetic Materials; Germ Cells; Goals; Haploidy; Imaging technology; Infertility; Investigation; Kinetochores; Lead; Learning; Link; Location; Meiosis; Microtubules; Mitosis; Mitotic; Molecular; Monitor; Patau' s syndrome; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Positioning Attribute; Process; Production; Proteins; Publishing; Quantitative Microscopy; Regulation; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Signal Transduction; Sister Chromatid; Site; Spontaneous abortion; System; Testing; Time; Trisomy; aurora B kinase; chromosome missegregation; egg; experimental study; genome integrity; human disease; innovation; insight; live cell imaging; novel; premature; prevent; programs; recruit; segregation; sperm cell; tool

Project Summary/Abstract: During meiosis, a diploid cell undergoes one round of replication followed by two rounds of chromosome segregation to ultimately produce haploid gametes. A failure to properly segregate chromosomes in meiosis can result in infertility, miscarriage, and trisomy conditions, such as Down syndrome. Despite the importance of meiosis, there is a lack of molecular understanding of how cell-cycle regulatory networks function to ensure that chromosomes properly attach to spindle microtubules in meiosis I and meiosis II. The objective of this proposal is to determine the mechanisms of meiotic regulation that ensure proper chromosome segregation in meiosis. These studies employ S. cerevisiae as the model organism due to the ease in developing tools to address mechanistic questions. These innovative tools will allow the investigation of how cells correct improper microtubule-kinetochore attachments, how cells set the duration of meiosis, and how crossover position along homologous chromosomes affect microtubule-kinetochore attachments. The rationale for the proposed research is that the questions were chosen to focus on processes that are likely to be highly conserved, allowing the findings in budding yeast to uncover general mechanisms of meiotic regulation. Strong preliminary data guided the following three specific aims: 1) Investigate how spindle checkpoint proteins crosstalk with kinases and phosphatases at the kinetochore to regulate the timing and fidelity of chromosome segregation in meiosis; 2) Determine how the spindle checkpoint is prematurely silenced during meiosis when chromosomes are not correctly attached to spindle microtubules; and, 3) Determine how crossover location along a chromosome can affect the fidelity of kinetochore-microtubule attachments. In the first aim, cell-cycle regulators at the kinetochore will be tested for their role in maintaining the timing and accuracy of meiosis. The second aim tests the novel hypothesis of a meiosis-specific mechanism for silencing the spindle checkpoint to ensure the formation of gametes, even without proper chromosome segregation. The third aim addresses the long unanswered question of why chromosomes with crossovers at sub-optimal positions are more likely to mis-segregate. Strains will be developed that have chromosomes engineered to form a crossover at a specific site and fast live cell imaging will monitor the attachment to microtubules. The innovative approach of combining the latest imaging technologies to monitor kinetochore-microtubule attachments in engineered strains allows the testing of novel hypotheses about cell-cycle regulation. The proposed research is significant because the results are expected to reveal general principles of meiotic regulation important for protecting genome integrity. Ultimately, the results will further our understanding of how errors in meiosis facilitate developmental abnormalities.

项目摘要/摘要： 在减数分裂期间，二倍体细胞经历一轮复制，然后进行两轮复制 染色体分离最终产生单倍体配子。未能正确分离染色体 减数分裂中的减数分裂可导致不孕、流产和三体性疾病，例如唐氏综合症。尽管 减数分裂的重要性，缺乏对细胞周期调控网络如何进行分子理解 其功能是确保染色体在减数分裂 I 和减数分裂 II 中正确附着在纺锤体微管上。这 该提案的目的是确定减数分裂调控机制，以确保正确的染色体 减数分裂中的分离。这些研究采用酿酒酵母作为模式生物，因为它易于 开发解决机械问题的工具。这些创新工具将允许调查如何 细胞纠正不正确的微管着丝粒附着，细胞如何设定减数分裂的持续时间，以及如何 沿同源染色体的交叉位置影响微管-着丝粒附着。理由 对于拟议的研究来说，问题的选择集中在可能高度复杂的过程上。 保守的，使得芽殖酵母的发现能够揭示减数分裂调节的一般机制。强的 初步数据指导了以下三个具体目标：1）研究纺锤体检查点蛋白如何 与动粒处的激酶和磷酸酶串扰，调节染色体的时间和保真度 减数分裂中的分离； 2) 确定在减数分裂过程中纺锤体检查点如何过早沉默 染色体未正确附着在纺锤体微管上；以及，3) 确定交叉位置 沿着染色体可以影响动粒-微管附着的保真度。第一个目标是细胞周期 将测试着丝粒的调节因子在维持减数分裂的时间和准确性方面的作用。这 第二个目标测试减数分裂特异性机制的新假设，该机制可沉默纺锤体检查点以 确保配子的形成，即使没有适当的染色体分离。第三个目标涉及 长期以来悬而未决的问题是，为什么在次优位置交叉的染色体更有可能 错误隔离。将开发出具有经过改造的染色体以在特定位置形成交叉的菌株。 位点和快速活细胞成像将监测微管的附着。的创新方法 结合最新的成像技术来监测工程中的着丝粒-微管附件 菌株可以测试有关细胞周期调节的新假设。拟议的研究意义重大 因为结果有望揭示减数分裂调控的一般原则，对于保护 基因组完整性。最终，这些结果将进一步加深我们对减数分裂错误如何促进的理解。 发育异常。