Defining PP1 phosphatase function in paternal meiotic chromosome segregation

定义 PP1 磷酸酶在父本减数分裂染色体分离中的功能

基本信息

批准号：
8101606
负责人：
Diana S. Chu
金额：
$ 46.02万
依托单位：
SAN FRANCISCO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101606
关键词：
Affect Anaphase Aneuploidy Animals Area Award Biological Assay Biology Caenorhabditis elegans Cell Cycle Progression Cells Centrosome Chromatin Chromosome Segregation Chromosome abnormality Chromosomes Chromosomes, Human, Pair 1 Clinic Clinical Complement Congenital Abnormality Development Developmental Biology Diagnostic Down Syndrome Ensure Equipment Event Exhibits Failure Future Generations Genetic Germ Cells Goals Health Hereditary Disease Homologous Gene Human Image Individual Infertility Kinesin Kinetochores Knowledge Laboratories Lateral Lead Life Mammals Meiosis Mental Retardation Metaphase Microtubules Minority-Serving Institution Mitosis Molecular Monitor Movement Oocytes Organism Pattern Phosphoric Monoester Hydrolases Preparation Process Proteins Reagent Regulation Reproductive Biology Research Research Project Grants Resolution Role Science Sister Chromatid Specific qualifier value Spermatocytes Spontaneous abortion Staging Structural Chromosomal Abnormality Students Testing Thinking Time Work career chromokinesin cohesin cohesion experience male migration molecular marker mutant offspring prevent reproductive reproductive success segregation sex skills sperm cell success transmission process

项目摘要

DESCRIPTION (provided by applicant): The leading causes of miscarriage and mental retardation in humans are chromosomal abnormalities, which can be generated by chromosome segregation errors during oocyte or sperm meiosis. The vast majority of de novo chromosomal structural abnormalities are of paternal origin; thus, it is vital to understand paternal chromosome segregation mechanisms to prevent both natural and assisted reproductive failure and the potential transmission of genetic diseases to offspring. We have identified the male-specific PP1 phosphatase homologs, GSP-3 and GSP-4, as the only known proteins with evolutionarily conserved function specifically in sperm formation from worms to humans. Our preliminary studies suggest that these phosphatases provide sex-specific regulation of chromosome orientation dynamics during the transition from meiosis I to meiosis II. GSP-3/4 localizes around sperm meiotic chromosomes in a pattern similar to that of kinetochore proteins, key connectors of chromosomes and microtubules. We also find GSP-3/4 regulate the sex-specific dynamic localization of specific kinetochore components. Thus, our hypothesis is that these PP1 phosphatases are key regulators of spindle microtubule attachment to chromatin and thus required for proper chromosome partitioning during sperm meiosis. We will test our hypothesis in three main areas: 1) chromosome orientation and microtubule dynamics during the MI to MII transition, 2) composition and dynamic localization of components of the kinetochore, and 3) localization of factors that modulate chromatin-microtubule interactions to orient chromosomes on the meiotic spindle. The proposed studies will identify molecular markers for sperm meiotic progression and paternal chromatin quality and content, which will further the fields of reproductive and developmental biology. Our team will also define the role of GSP-3/4 and key regulators of meiosis at specific stages of paternal chromosome segregation, making a significant contribution to the field of chromosome biology. This research will lay the groundwork for future development of clinical diagnostics and therapies to identify or prevent paternally-derived chromosomal abnormalities, a vital step to ensuring reproductive success and the health of future offspring. These studies will incorporate the diverse undergraduate and master's level students at SFSU, a historically minority-serving institution. We anticipate 2-3 students per year will conduct individual research projects using well-characterized reagents and assays with newly acquired cutting-edge equipment during the three-year award period. As such, they will gain hands-on, relevant research experience and critical thinking skills to further their careers in the biomedical sciences. PUBLIC HEALTH RELEVANCE: The leading causes of mental retardation and miscarriages in humans are chromosomal abnormalities generated during either oocyte or sperm meiosis. Determining the molecular mechanisms that govern paternal meiotic chromosome segregation is thus crucial to understanding how miscarriage, infertility, and birth defects like Down's Syndrome arise. This study will contribute to the eliminating a considerable gap in knowledge in how meiotic chromosome segregation is regulated in sex-specific ways to ensure reproductive and developmental success.

描述（申请人提供）：人类流产和智力低下的主要原因是染色体异常，这种异常可能是由卵母细胞或精子减数分裂过程中的染色体分离错误引起的。绝大多数从头染色体结构异常都是父系起源的；因此，了解父本染色体分离机制对于预防自然和辅助生殖失败以及遗传疾病潜在地传播给后代至关重要。我们已经鉴定出男性特异性 PP1 磷酸酶同源物 GSP-3 和 GSP-4，它们是唯一已知的具有进化保守功能的蛋白质，特别是在从蠕虫到人类的精子形成过程中。我们的初步研究表明，这些磷酸酶在从减数分裂 I 到减数分裂 II 的过渡过程中提供性别特异性的染色体取向动态调节。 GSP-3/4 以类似于动粒蛋白（染色体和微管的关键连接器）的模式定位在精子减数分裂染色体周围。我们还发现 GSP-3/4 调节特定着丝粒成分的性别特异性动态定位。因此，我们的假设是，这些 PP1 磷酸酶是纺锤体微管附着于染色质的关键调节因子，因此是精子减数分裂期间正确染色体分配所必需的。我们将在三个主要领域检验我们的假设：1）MI 到 MII 过渡期间的染色体定向和微管动力学，2）着丝粒成分的组成和动态定位，以及 3）调节染色质-微管相互作用以定向的因素的定位减数分裂纺锤体上的染色体。拟议的研究将确定精子减数分裂进程和父本染色质质量和含量的分子标记，这将进一步推动生殖和发育生物学领域的发展。我们的团队还将明确GSP-3/4和减数分裂在父本染色体分离特定阶段的关键调节因子的作用，为染色体生物学领域做出重大贡献。这项研究将为未来临床诊断和治疗的发展奠定基础，以识别或预防父源染色体异常，这是确保生殖成功和未来后代健康的重要一步。这些研究将纳入 SFSU（一所历史上为少数族裔服务的机构）的不同本科生和硕士生。我们预计每年有 2-3 名学生将在三年奖励期内使用特性良好的试剂和新购置的尖端设备进行分析来开展个人研究项目。因此，他们将获得实践、相关的研究经验和批判性思维技能，以进一步推动他们在生物医学领域的职业生涯。公共卫生相关性：人类智力低下和流产的主要原因是卵母细胞或精子减数分裂过程中产生的染色体异常。因此，确定控制父系减数分裂染色体分离的分子机制对于理解流产、不孕症和唐氏综合症等出生缺陷是如何产生的至关重要。这项研究将有助于消除在如何以性别特异性方式调节减数分裂染色体分离以确保生殖和发育成功方面的巨大知识空白。