Synaptonemal Complex Assembly and Function in Meiosis

减数分裂中的联会复合体组装和功能

基本信息

批准号：
8116407
负责人：
Monica P Colaiacovo
金额：
$ 33.98万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116407
关键词：
3-Dimensional Accounting Address Architecture Area Biochemical Biochemical Process Biological Assay Biological Models Caenorhabditis elegans Cell Division Process Cell division Chromosome Pairing Chromosome Segregation Chromosomes Chromosomes, Human, Pair 1 Clinical Congenital Abnormality DNA Damage DNA biosynthesis Development Diploidy Down Syndrome Eukaryota Failure Fertilization Foundations Funding Genes Genetic Genetic Nondisjunction Genetic Recombination Genetic Variation Germ Cells Goals Haploidy Homologous Gene Human Lead Meiosis Meiotic Recombination Molecular Molecular Analysis Molecular Conformation Molecular Genetics Nematoda Nuclear Optic Chiasm Pathway interactions Phosphoric Monoester Hydrolases Play Ploidies Prevention strategy Process Production Proteins Proteomics RNA Interference Regulation Reproduction Research Role Series Sister Chromatid Site Spontaneous abortion Structure Synapses Synaptonemal Complex System Work Yeasts aurora B kinase cohesion egg functional genomics genetic regulatory protein in vitro Assay in vivo insight macromolecular assembly mutant novel polymerization premature programs protein function public health relevance reconstitution response sperm cell yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Meiosis is a specialized cell division process that results in the formation of haploid gametes (i.e.: eggs and sperm) and is therefore essential for sexual reproduction and generating genetic diversity. The reduction of the chromosome complement by half is accomplished by following a single round of DNA replication with two consecutive rounds of chromosome segregation (meiosis I and meiosis II). Achieving accurate chromosome segregation is paramount for the successful formation of haploid gametes. To segregate properly, chromosomes must undergo a series of steps that are unique to meiosis I, including: (1) homologous pairing, (2) formation of a "zipper-like" structure (the synaptonemal complex or SC) between aligned homologs, and (3) completion of meiotic recombination leading to physical attachments (chiasmata) between homologs. Significantly, errors in any of these steps lead to chromosome nondisjunction, with disastrous consequences including miscarriages and birth defects such as Down syndrome. Our goal is to investigate the roles, macromolecular assembly and regulation of the SC, whose functions are poorly understood and a matter of much debate despite its ubiquitous presence from yeast to humans. Focusing on this goal will reveal how synapsis intersects with the regulation of meiotic progression and promotes accurate chromosome segregation. We are addressing this important issue by studying it in the nematode C. elegans, an ideal model system for meiotic studies, amenable to various genetic, molecular, biochemical and cytological approaches. We have recently identified four critical SC components (SYP-1, SYP-2, SYP-3 and SYP-4), proteins that regulate SC assembly (CRA-1), meiotic recombination (HIM-18), and SC disassembly and sister chromatid cohesion during meiosis I (LAB-1). Beginning with the analysis of the molecular mechanisms through which several of these proteins function during meiosis, we propose to address the fundamental issues of how pairing, synapsis and recombination intersect and are regulated resulting in accurate chromosome segregation. We will do this by combining cytological observations done in the context of an intact 3-D nuclear architecture in this system, with results from molecular, genetic and biochemical approaches. Taken together, this application will provide significant new insights into the molecular mechanisms underlying accurate meiotic chromosome segregation and move us forward in our understanding of analogous processes in higher eukaryotes. PUBLIC HEALTH RELEVANCE: Meiosis is a specialized cell division program required for the production of eggs and sperm and therefore essential for human reproduction. Errors during meiosis are predicted to account for approximately 35% of all miscarriages in humans and birth defects such as Down syndrome. The proposed research will investigate the molecular mechanisms promoting accurate meiotic chromosome segregation thereby laying the foundation for the development of effective preventive strategies.

描述（由申请人提供）：减数分裂是一种专门的细胞分裂过程，导致形成单倍体配子（即鸡蛋和精子），因此对于有性繁殖和产生遗传多样性至关重要。染色体补体的减少一半是通过跟随一轮DNA复制来实现的，并连续两轮染色体分离（减数分裂I和减数分裂II）。实现准确的染色体隔离对于成功形成单倍配子至关重要。为了正确隔离，染色体必须执行一系列减数分裂I的步骤，包括：（1）同源性同源物之间的“ Zipper样”结构（同型同源物之间的“ Zipper样”结构（SYNAPTONEMAL COPPLECT或SC）的形成，以及（3）在物理附着（chiasmata）之间的减数分裂重组之间的完成（3）。值得注意的是，这些步骤中的任何一个中的错误导致染色体非分离，并带来灾难性的后果，包括流产和诸如唐氏综合症之类的先天缺陷。我们的目标是研究SC的角色，大分子组装和调节，尽管其功能鲜为人知，尽管从酵母到人类到人类的存在无处不在，但其功能很广泛。关注这个目标将揭示突触如何与减数分裂进程的调节相交并促进准确的染色体分离。我们正在通过在线虫C.秀拉斯（C. Elegrans）中进行研究，这是一种减数分裂研究的理想模型系统，可以解决这一重要问题，适合各种遗传，分子，生化和细胞学方法。我们最近确定了调节SC组装（CRA-1），减数分裂重组（HIM-18）以及SC拆卸和姐妹染色体凝聚力的四个关键SC分量（SYP-1，SYP-2，SYP-2，SYP-3和SYP-4），调节SC组装（CRA-1），减数分裂重组（HIM-18）的蛋白质。从分子机制的分析开始，这些蛋白质中的几种在减数分裂过程中起作用，我们建议解决配对，突触和重组如何相交的基本问题并受到调节，从而导致准确的染色体分离。我们将通过结合在该系统完整的3-D核结构的背景下进行的细胞学观察来做到这一点，并由分子，遗传和生化方法进行。综上所述，该应用将为准确的减数分裂染色体隔离的分子机制提供重要的新见解，并在对较高真核生物中类似过程的理解中前进。公共卫生相关性：减数分裂是产生卵和精子所需的专门细胞分裂程序，因此对于人类繁殖至关重要。预计减数分裂过程中的错误将占人类所有流产的35％和诸如唐氏综合症之类的先天缺陷。拟议的研究将研究促进准确的减数分裂染色体分离的分子机制，从而为开发有效的预防策略奠定了基础。