Regulation of Synaptonemal Complex Assembly During Meiosis in S. cerevisiae

描述(申请人提供)：在减数分裂开始时，染色体启动广泛的重组，最终形成对齐的同源染色体，由联会复合体(SC)沿长度连接，每个染色体都能够与其伴侣进行重组。这一过程对于有性生殖生物体配子形成过程中准确的染色体分离是至关重要的。尽管在不同的生物中观察了一个多世纪的减数分裂染色体配对和突触，但基本减数分裂染色体事件背后的分子机制仍然不清楚。同源染色体如何相互识别？这种最初的认识是如何得到加强的？同源识别如何与SC组装协调，从而使突触特定地发生在成对的染色体之间？我已经开始通过筛选调控萌芽酵母中SC组装的因素来研究这些问题。我确定了两个因素在SC监管中的作用。FPR3基因促进同源比对有缺陷的核中形成多复合体。多复合体是SC组分在染色体上的局部聚集，反映了SC聚合在染色体上的失败，经常出现在配对或重组中出现早期减数分裂缺陷的突变体中。另一方面，ZIP在阻止SC在染色体上组装方面起到了作用。当多复合体的形成受到影响并且zips活性缺失时(如在zips fprs双突变体中)，SC组分在染色体上聚合，而与同源排列无关。有趣的是，在ZIP FPR核中出现的线性SC结构起源于着丝粒区域。由于ZIPPS与SC结构成分ZIP1在同源基因比对之前的着丝粒区域共定位，可能ZIPPS通过调节着丝粒上的SC组装而有助于加强同源基因的识别。提出的实验使用遗传学、细胞学和蛋白质组学的方法来问：FPR和ZIP是如何调节SC组装的？SC组装、重组和同源配对之间的分子关系是什么？这项拟议的研究旨在了解控制酵母和哺乳动物之间保守的减数分裂染色体过程的基本细胞机制。由于减数分裂染色体分离缺陷会导致不孕不育和唐氏综合症等疾病，希望我的研究成果能对理解、治疗和培育人类生殖健康起到作用。

DESCRIPTION (provided by applicant): At the start of meiosis, chromosomes initiate an extensive reorganization that culminates in aligned homologous chromosomes, joined along their lengths by synaptonemal complex (SC), and each capable of undergoing recombination with its partner. This process is critical for accurate chromosome segregation during gamete formation in sexually reproducing organisms. Despite over a century of observing meiotic chromosome pairing and synapsis in diverse organisms, the molecular mechanisms underlying fundamental meiotic chromosomal events are still unknown. How do homologous chromosomes identify one another? How is this initial recognition reinforced? How is homolog recognition coordinated with SC assembly, such that synapsis occurs specifically between paired chromosomes? I have begun to investigate these questions by screening for factors that regulate SC assembly in budding yeast. I identified roles for two factors in SC regulation. The FPR3 gene promotes the formation of polycomplexes in nuclei that are defective in homolog alignment. Polycomplexes are focal accumulations of SC components that reflect a failure in SC polymerization on chromosomes, and frequently occur in mutants with early meiotic defects in pairing or recombination. ZIPS, on the other hand, plays a role in preventing SC assembly on chromosomes. When polycomplex formation is compromised and ZIPS activity is missing, (as in a zipS fprS double mutant), SC components polymerize on chromosomes, independent of homolog alignment. Interestingly, the linear SC structures that arise in zipS fprS nuclei originate from centromere regions. As ZipS colocalizes with the SC structural component, Zip1, at centromere regions prior to homolog alignment, perhaps ZipS contributes to reinforcing homolog recognition by regulating SC assembly at centromeres. The experiments proposed use genetic, cytological and proteomic approaches to ask: How do FPRS and ZIPS regulate SC assembly? What is the molecular relationship between SC assembly, recombination and homolog pairing? The proposed research aims to understand basic cellular mechanisms that control meiotic chromosome processes that are conserved between yeast and mammals. As meiotic chromosome segregation defects lead to infertility and disorders such as Down's Syndrome, it is hoped that what is learned from my research may play a role in understanding, treating, and nurturing human reproductive health.