Synaptonemal complex assembly and function in meiosis

 描述（由申请人提供）：在减数分裂期间未能实现准确的染色体分离可导致流产、不育、肿瘤发生和出生缺陷，如唐氏综合征。从二倍体生殖细胞成功产生单倍体配子（即卵子和精子）对生殖健康的明确和显著影响使得了解减数分裂期间准确染色体分离的机制至关重要。减数分裂的一个普遍存在但知之甚少的特征是拉链状结构，称为联会复合体（SC）。已知SC稳定同源配对相互作用，对于同源物之间的交换形成是必不可少的，并且因此是减数分裂I时正确的染色体分离所必需的。然而，调控SC组装和拆卸的机制，以及随着SC拆卸而启动的精心策划的染色体重塑过程，在任何生物体中都没有得到很好的理解。我们的目标是通过利用线虫C的遗传、细胞学、分子和生化分析的便利性来解决这些关键问题。elegans是种系研究的理想模型系统。我们在上一个资助期间取得的进展，加上新的数据和技术，揭示了几个分子切入点，使我们处于了解染色体突触和染色体重塑调控的理想位置。在这里，我们提出了一套三个综合目标，以解决这些关键的生物过程。目的1将解决NatB介导的减数分裂蛋白的N-末端乙酰化如何调节SC组装;这将集中于调节真核生物中由高度普遍的共翻译修饰驱动的染色体突触的新机制，但迄今为止很少有生物学功能被归因于此。目的2将确定GRAS-1的功能机制，GRAS-1是一种新的保守蛋白，具有以前未知的减数分裂功能，我们的研究暗示其调节SC组装，我们假设其可能作为SC结构组分的分子支架。目的3将确定MAP激酶途径如何调节SC组装、拆卸和染色体重塑;这个目标将结合我们对ECT-2（人Rho鸟嘌呤核苷酸交换因子的同源物）的发现，以研究MAP激酶途径如何调节减数分裂后期前期的突触和染色体重塑。这些研究将为我们理解SC组装、拆卸和染色体重塑的调控机制提供新的思路。我们的研究有望影响与人类健康密切相关的多个领域，包括染色体动力学，共翻译修饰研究，大分子结构调控和信号转导。两者合计，这一应用将提供重要的新的见解，在减数分裂过程中精确的染色体分离的分子调控机制。

 DESCRIPTION (provided by applicant): Failure to achieve accurate chromosome segregation during meiosis can lead to miscarriages, infertility, tumorigenesis and birth defects such as Down syndrome. The clear and significant impact to reproductive health of successfully producing haploid gametes (i.e. eggs and sperm) from diploid germ cells makes it of paramount importance to understand the mechanisms underlying accurate chromosome segregation during meiosis. A ubiquitously present, and yet poorly understood, feature of meiosis is the zipper-like structure known as the synaptonemal complex (SC). It is known that the SC stabilizes homologous pairing interactions, is essential for crossover formation between homologs, and therefore, required for proper chromosome segregation at meiosis I. However, the mechanisms regulating SC assembly and disassembly, as well as the orchestrated chromosome remodeling process that initiates as the SC disassembles, are not well understood in any organism. Our goal is to address these critical issues by taking advantage of the ease of genetic, cytological, molecular and biochemical analysis that is afforded by the use of the nematode C. elegans, an ideal model system for germline studies. Our progress during the previous funding period, coupled with new data and technology, has revealed several molecular entry points that place us in an ideal position to understand the regulation of chromosome synapsis and chromosome remodeling. Here we propose a set of three integrated aims to address these critical biological processes. Aim 1 will address how NatB-mediated N- terminal acetylation of meiotic proteins regulates SC assembly; this will focus on a new mechanism for regulating chromosome synapsis driven by a highly prevalent co-translational modification in eukaryotes, but for which very few biological functions have been ascribed so far. Aim 2 will determine the mechanisms of function for GRAS-1, a new and conserved protein of previously unknown meiotic function, which our studies implicate in regulating SC assembly and we hypothesize may act as a molecular scaffold for structural components of the SC. Aim 3 will define how the MAP kinase pathway regulates SC assembly, disassembly, and chromosome remodeling; this aim will incorporate our discovery of ECT-2, the homolog of human Rho guanine nucleotide exchange factor, to examine how the MAP kinase pathway modulates synapsis and chromosome remodeling in late meiotic prophase. These studies will shed new light on our understanding of the mechanisms regulating SC assembly, disassembly and chromosome remodeling. Our studies are expected to impact multiple fields of tremendous relevance to human health including chromosome dynamics, the study of co-translational modifications, regulation of macromolecular structures and signal transduction. Taken together, this application will provide significant new insights into the molecular mechanisms regulating accurate chromosome segregation during meiosis.