Characterization of a Meiotic Crossover Surveillance System

减数分裂交叉监视系统的表征

基本信息

批准号：
10219811
负责人：
JUDITH L YANOWITZ
金额：
$ 27.83万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219811
关键词：
Accounting Address Aneuploidy Appearance Biochemical Cell Cycle Progression Cell Nucleus Cell division Chromosome Pairing Chromosome Segregation Chromosomes Communication Congenital Abnormality Couples Coupling Defect Diagnosis Dissection Drosophila polo protein Ensure Etiology Event Genes Genetic Crossing Over Genetic Epistasis Genetic Materials Genetic Recombination Genetic Screening Genome Stability Germ Cells Habitual Abortion Homologous Gene Image Infertility Inherited Intervention Lead Link Male Infertility Mediating Meiosis Membrane Proteins Metaphase Microscopic Microscopy Modification Molecular Monitor Nuclear Envelope PLK1 gene Phosphoric Monoester Hydrolases Phosphorylation Positioning Attribute Premature Ovarian Failure Process Prophase Proteins Reporting Resolution Risk Factors Role Signal Transduction Signaling Molecule Spontaneous abortion Synaptonemal Complex System Termination of pregnancy Therapeutic Intervention Time Transmission Electron Microscopy age related chromosome movement egg fascinate in vivo insight novel repaired scaffold segregation sperm cell tool

项目摘要

PROJECT SUMMARY During the formation of egg and sperm, the maternally- and paternally-inherited chromosomes exchange genetic material in the process known as meiotic crossover recombination. Crossing over creates a transient, physical connection between the homologs that helps them align at metaphase and segregate to opposite poles. Without crossing over, homologs segregate randomly which can lead to aneuploidy, a condition associated with birth defects and miscarriage. The importance of crossover formation is underscored by the extensive crosstalk between meiotic events that ensures their timely and orderly completion. We recently identified a chromosome-by-chromosome surveillance system that couples crossover formation to timely meiotic progression and to stabilization of the synaptonemal complex (SC), a molecular scaffold that stably juxtaposes homologous chromosomes. The first crossover intermediate activates a systemic signal that both changes the dynamics of the SC on the other chromosomes, making them meta-stable, and also promotes chromosome mobility to potentiate crossover formation. We identified the nuclear membrane protein SUN-1 and the polo-like kinase, PLK-2, as key effectors of these signals. The current proposal expands our characterization of the surveillance system to provide mechanistic insight into these processes. Genetic screens will be used to identify the crossover intermediates that are recognized by the surveillance system and the signaling molecules that communicate this to the progression machinery and SC. Using a combination of biochemical and advanced microscopic approaches, we will dissect out the changes that occur to the SC upon activation of the surveillance system and how this regulates crossover formation. We will also further delineate the roles of SUN-1 and PLK-2 in the surveillance system. These studies will increase our understanding of cellular mechanisms that promote genome stability through the monitoring of crossover intermediates. These studies can provide insight into the etiology of birth defects, recurrent miscarriage, premature ovarian failure and male infertility, opening avenues for diagnosis and therapeutic intervention.

项目摘要在形成鸡蛋和精子的过程中，孕妇和亲属染色体交换在称为减数分裂跨界重组的过程中的遗传物质。越过会产生瞬态，同源物之间的物理连接有助于它们在中期对齐并隔离到相对杆。在不跨越的情况下，同源物随机分离，这可能导致非整倍性，条件与先天缺陷和流产有关。交叉形成的重要性由减数分裂事件之间的广泛串扰确保了他们及时，有序地完成。我们最近确定了一个逐染色体的染色体监视系统，该系统将跨界形成与及时形成减数分裂进程和突触复合物（SC）的稳定，这是一个稳定的分子支架并置同源染色体。第一个跨界中间体激活了一个全身信号改变其他染色体上SC的动态，使其稳定，也可以促进染色体的迁移率增强了跨界形成。我们确定了核膜蛋白太阳-1 以及类似马球的激酶PLK-2作为这些信号的关键效应子。当前的提议扩大了我们的监视系统的表征，以提供对这些过程的机械洞察力。遗传屏幕将用于识别监视系统识别的跨界中间体将其传达给进展机械和SC的信号分子。结合生化和先进的微观方法，我们将剖析SC上发生的变化监视系统的激活以及如何调节交叉形成。我们还将进一步描述 Sun-1和PLK-2在监视系统中的作用。这些研究将增加我们对通过监测跨界中间体来促进基因组稳定性的细胞机制。这些研究可以提供有关先天缺陷，反复流产，卵巢过早失败的病因的洞察力和男性不育症，开放诊断和治疗干预的途径。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A twist of fate: How a meiotic protein is providing new perspectives on germ cell development.

命运的转折：减数分裂蛋白如何为生殖细胞发育提供新的视角。

DOI：
10.1080/21624054.2016.1175259
发表时间：
2016
期刊：
Worm
影响因子：
0
作者：
Mainpal,Rana;Yanowitz,JudithL
通讯作者：
Yanowitz,JudithL

The molecular tug of war between immunity and fertility: Emergence of conserved signaling pathways and regulatory mechanisms.

DOI：
10.1002/bies.202000103
发表时间：
2020-12
期刊：
BioEssays : news and reviews in molecular, cellular and developmental biology
影响因子：
0
作者：
Naim N;Amrit FRG;McClendon TB;Yanowitz JL;Ghazi A
通讯作者：
Ghazi A

Cytogenetic signatures of recurrent pregnancy losses.

DOI：
10.1002/pd.5838
发表时间：
2021-01
期刊：
Prenatal diagnosis
影响因子：
3
作者：
Yatsenko SA;Quesada-Candela C;Saller DN;Beck S;Jaffe R;Kostadinov S;Yanowitz J;Rajkovic A
通讯作者：
Rajkovic A

Methodological considerations for mutagen exposure in C. elegans.

线虫诱变剂暴露的方法学考虑。