Meiotic Functions of Mps1

Mps1 的减数分裂功能

• 批准号: 0950005
• 负责人: Dean Dawson
• 金额: $ 29.23万
• 依托单位: Oklahoma Medical Research Foundation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0950005&HistoricalAwards=false
• 关键词: Meiotic; Functions; Mps1

During the growth of somatic cells, mitotic divisions partition one copy of each chromosome to each daughter cell. The production of gametes requires a special form of chromosome partitioning, meiosis, in which two sequential rounds chromosome segregation yield gametes with half the number of chromosomes of the somatic cells. The meiotic process is accomplished in part by layering specialized levels of meiosis-specific control upon the cellular machinery that is used for mitosis. Identifying these meiosis-specific controls is central to deciphering the mechanisms that are used to achieve high fidelity chromosome segregation in meiosis. MPS1 encodes a conserved, essential, kinase that has been shown be involved in several key steps in chromosome segregation in both mitotic and meiotic cells in many species. Mps1 is involved in: 1) duplication of the spindle pole body (in budding yeast), the structure that organizes the assembly of microtubules into the spindle that will pull the segregating chromosomes apart, 2) participation in the spindle assembly checkpoint mechanism that signals to the cell that a chromosome is attached inappropriately to microtubules, 3) mediating the release of these inappropriate attachments so that new ones can form, and 4) (in budding yeast) promoting the proper assembly of spore walls. Because of the multiple roles of Mps1 protein, MPS1 mutants often have complex phenotypes that are not informative for genetic studies. The recent discovery of a specific mutation, mps1-R170S has opened the door to exploring meiosis-specific roles for Mps1. mps1-R170S mutants have very mild defects in mitotic growth but catastrophic defects in chromosome segregation in meiosis. msp1-R170S mutants exhibit very high levels of chromosome segregation errors in both the first and second meiotic division. Thus the mps1-R170S destroys only some functions of Mps1 (meiosis-specific functions) and provides the opportunity to study those defects in ways that should reveal the role of the Mps1 protein in meiosis. Preliminary data suggest two hypotheses for the role of Mps1 in meiosis. This project will test these hypotheses. Either hypothesis, or a combination of the two, would explain the observed meiotic behavior mps1-R170S mutants. The first hypothesis is that Mps1 plays an essential meiotic role in dissolving kinetochore-microtubule attachments. By this hypothesis, kinetochores are attached early in both meiotic divisions to microtubules from only one spindle pole body and Mps1 is required to release these attachments so that attachments to both spindle pole bodies can be formed. The second hypothesis is that Mps1 is required to release an association between sister chromatids in meiosis. According to this hypothesis a persistent association of sister chromatids locks homologous chromosomes together in meiosis I, forcing them to move together to one spindle pole at meiosis I, and forcing sister chromatids to move to one pole at meiosis II. A final objective of this proposal is to use genetic approaches to identify the partners with which Mps1 interacts in meiosis.Broader Impacts: Because Mps1 is highly conserved, these studies of Mps1 in yeast meiosis may reveal general principles of Mps1 function, and mitotic and meiotic chromosome behavior, that are widely applicable to most eukaryotic organisms. The project will provide a training opportunity for one post-doctoral researcher. In addition, this project will be used to provide summer students, from a local high school and undergraduate training program, with independent research projects. In this program the students will learn fundamentals of genetics while contributing to the analysis of genes that interact with Mps1 in meiosis. The post-doctoral researcher will not only perform most of the experiments on the project but will serve as comentor for the undergraduate/high school trainees.

在体细胞的生长过程中，有丝分裂将每条染色体的一份副本分配给每个子细胞。配子的产生需要一种特殊形式的染色体分配，即减数分裂，其中连续两轮染色体分离产生的配子的染色体数量是体细胞的一半。减数分裂过程部分是通过对用于有丝分裂的细胞机器进行减数分裂特异性控制的分层来完成的。识别这些减数分裂特异性控制对于破译用于在减数分裂中实现高保真度染色体分离的机制至关重要。 MPS1 编码一种保守的必需激酶，已证明该激酶参与许多物种有丝分裂和减数分裂细胞中染色体分离的几个关键步骤。 MPS1 参与：1) 纺锤体极体的复制（在芽殖酵母中），该结构将微管组装到纺锤体中，将分离的染色体拉开，2) 参与纺锤体组装检查点机制，向染色体不恰当地附着在微管上的细胞，3）介导这些不恰当附着物的释放，以便形成新的附着物，4）（在芽殖酵母中）促进适当的附着物孢子壁的组装。由于 Mps1 蛋白的多重作用，MPS1 突变体通常具有复杂的表型，无法为遗传学研究提供信息。最近发现的特定突变 mps1-R170S 为探索 Mps1 减数分裂特异性作用打开了大门。 mps1-R170S 突变体在有丝分裂生长方面具有非常轻微的缺陷，但在减数分裂中的染色体分离方面具有灾难性的缺陷。 msp1-R170S 突变体在第一次和第二次减数分裂中都表现出非常高水平的染色体分离错误。因此，mps1-R170S 仅破坏了 Mps1 的一些功能（减数分裂特异性功能），并提供了以揭示 Mps1 蛋白在减数分裂中的作用的方式研究这些缺陷的机会。初步数据提出了关于 Mps1 在减数分裂中的作用的两种假设。该项目将测试这些假设。任一假设或两者的组合都可以解释观察到的 mps1-R170S 突变体的减数分裂行为。第一个假设是 Mps1 在溶解着丝粒-微管附着物中起着重要的减数分裂作用。根据这一假设，动粒在两次减数分裂早期都附着在来自仅一个纺锤体极体的微管上，并且需要 Mps1 来释放这些附着物，以便可以形成对两个纺锤体极体的附着。第二个假设是，减数分裂中需要 Mps1 来释放姐妹染色单体之间的关联。根据这一假设，姐妹染色单体的持续关联在减数分裂 I 中将同源染色体锁在一起，迫使它们在减数分裂 I 时一起移动到一个纺锤体极，并迫使姐妹染色单体在减数分裂 II 时移动到一个纺锤极。该提案的最终目标是使用遗传方法来识别 Mps1 在减数分裂中相互作用的伙伴。 更广泛的影响：由于 Mps1 高度保守，因此对酵母减数分裂中 Mps1 的这些研究可能揭示 Mps1 功能以及有丝分裂和减数分裂的一般原理染色体行为，广泛适用于大多数真核生物。该项目将为一名博士后研究员提供培训机会。此外，该项目还将用于为当地高中和本科生培训项目的暑期学生提供独立研究项目。在这个项目中，学生将学习遗传学基础知识，同时有助于分析减数分裂中与 Mps1 相互作用的基因。博士后研究员不仅将执行该项目的大部分实验，还将担任本科/高中学员的导师。