Synaptonemal Complex Assembly and Function in Meiosis

描述（由申请人提供）：减数分裂是一种特殊的细胞分裂过程，导致单倍体配子（即卵子和精子）的形成，因此对有性生殖和产生遗传多样性至关重要。染色体补体减少一半是通过连续两轮染色体分离（减数分裂I和减数分裂II）进行单轮DNA复制来完成的。实现准确的染色体分离对单倍体配子的成功形成至关重要。为了正确分离，染色体必须经历减数分裂I特有的一系列步骤，包括：(1)同源配对，(2)在对齐的同源物之间形成“拉链状”结构（突触复合体或SC），以及(3)完成减数分裂重组，导致同源物之间的物理附着（交叉）。值得注意的是，这些步骤中的任何一个错误都会导致染色体不分离，导致灾难性的后果，包括流产和出生缺陷，如唐氏综合症。我们的目标是研究SC的作用、大分子组装和调控，尽管它从酵母到人类无处不在，但其功能却鲜为人知，而且存在许多争议。关注这一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。我们正在通过研究秀丽隐杆线虫来解决这一重要问题，秀丽隐杆线虫是减数分裂研究的理想模型系统，适用于各种遗传，分子，生化和细胞学方法。我们最近确定了四个关键的SC成分（SYP-1, SYP-2， SYP-3和SYP-4），以及在减数分裂I期间调节SC组装（CRA-1），减数分裂重组（hm -18）和SC拆卸和姐妹染色单体内聚的蛋白质（LAB-1）。从分析这些蛋白质在减数分裂过程中发挥作用的分子机制开始，我们提出解决配对，突触和重组如何交叉和调节导致准确染色体分离的基本问题。我们将通过结合在该系统中完整的3-D核结构背景下进行的细胞学观察，以及分子，遗传和生化方法的结果来做到这一点。总之，这一应用将为精确减数分裂染色体分离的分子机制提供重要的新见解，并推动我们对高等真核生物类似过程的理解。

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.