Regulation of chromosome synapsis in mice

描述（由申请人提供）：本申请的长期目标是研究我们实验室最近鉴定的新型蛋白质复合物对小鼠染色体突触的调节。减数分裂异常是导致人类出生缺陷和不育的主要原因。减数分裂染色体末端（端粒）附着在核膜上，以及减数分裂前期早期染色体的快速移动，促进了染色体联会。虽然肌动蛋白细胞骨架是必不可少的动态运动的减数分裂染色体在芽殖酵母，肌动蛋白依赖的动力，负责染色体运动的任何生物体的性质还没有被理解。我们以前确定Tex 19作为小鼠生殖细胞特异性基因，编码一种功能未知的小蛋白（351 aa）。现在我们已经发现TEX 19调节染色体突触。我们还发现，TEX 19与泛素E3连接酶UBR 2（一种N-末端规则蛋白水解途径的泛素E3连接酶）和睾丸中的肌动蛋白马达蛋白肌球蛋白II形成紧密复合物。因此，我们假设TEX 19通过与泛素E3连接酶UBR 2和肌动蛋白马达蛋白肌球蛋白II的结合来调节减数分裂染色体运动和染色体突触。我们建议通过以下实验策略来验证这一假设。在具体目标1中，我们将研究TEX 19-UBR 2和TEX 19-肌球蛋白II复合物调节染色体突触的分子机制。在具体目标2，我们计划阐明肌动蛋白马达蛋白肌球蛋白II和肌动蛋白丝在减数分裂染色体突触和染色体运动通过遗传和时间推移成像分析的作用。生物化学，遗传学，细胞生物学和延时成像方法的创新组合将提供对小鼠减数分裂染色体运动调节机制的深入了解，这在很大程度上尚未探索。 公共卫生相关性：减数分裂异常是人类不育和出生缺陷（三体和单体）的主要原因。该项目的完成将使人们深入了解人类男性不育和出生缺陷的病因。

DESCRIPTION (provided by applicant): The long-term objective of the current application is to study the regulation of chromosomal synapsis in mice by novel protein complexes recently identified in our laboratory. Abnormality in meiosis is a leading cause of birth defects and infertility in humans. Chromosomal synapsis is facilitated by the attachment of meiotic chromosome ends (telomeres) to the nuclear envelope and by rapid movements of meiotic chromosomes during early prophase I. While actin cytoskeleton is essential for dynamic movements of meiotic chromosomes in budding yeast, the nature of the actin-dependent motive force responsible for chromosome movement in any organism is not yet understood. We previously identified Tex19 as a germ cell-specific gene in mice that encodes a small protein (351 aa) of unknown function. Now we have found that TEX19 regulates chromosomal synapsis. We have also found that TEX19 forms a tight complex with ubiquitin E3 ligase UBR2, an ubiquitin E3 ligase of the N-end rule proteolysis pathway, and actin motor protein myosin II in the testis. Therefore, we hypothesize that TEX19 modulates meiotic chromosome movement and chromosomal synapsis through its association with ubiquitin E3 ligase UBR2 and the actin motor protein myosin II. We propose to test this hypothesis through the following experimental strategies. In Specific Aim 1, we will investigate the molecular mechanisms by which TEX19-UBR2 and TEX19-myosin II complexes regulate chromosomal synapsis. In Specific Aim 2, we plan to elucidate the role of the actin motor protein myosin II and actin filaments in meiotic chromosomal synapsis and chromosome movements through genetic and time-lapse imaging analyses. An innovative combination of biochemical, genetic, cell biological, and time-lapse imaging approaches will provide insights into the mechanisms underlying the regulation of meiotic chromosome movements in mice, which has remained largely unexplored. PUBLIC HEALTH RELEVANCE: Abnormalities in meiosis are a leading cause of both infertility and birth defects (trisomy and monosomy) in humans. Completion of this project will provide insight into the etiology of male infertility and birth defects in humans.