Regulation of chromosome synapsis in mice

描述（由申请人提供）：当前申请的长期目标是通过我们实验室最近发现的新型蛋白质复合物来研究小鼠染色体突触的调节。减数分裂异常是人类出生缺陷和不孕症的主要原因。染色体突触是由减数分裂染色体末端（端粒）附着到核膜和减数分裂染色体在早期前期的快速运动所促进的。虽然肌动蛋白细胞骨架对出芽酵母减数分裂染色体的动态运动是必不可少的，但在任何生物体中负责染色体运动的肌动蛋白依赖的动力的性质尚不清楚。我们之前在小鼠中发现Tex19是一个生殖细胞特异性基因，它编码一个功能未知的小蛋白（351 aa）。现在我们发现TEX19调控染色体突触。我们还发现TEX19在睾丸中与泛素E3连接酶UBR2、n端规则蛋白水解途径的泛素E3连接酶和肌动蛋白运动蛋白myosin II形成紧密复合物。因此，我们假设TEX19通过与泛素E3连接酶UBR2和肌动蛋白运动蛋白myosin II的关联来调节减数分裂染色体的运动和染色体突触。我们建议通过以下实验策略来验证这一假设。在Specific Aim 1中，我们将研究TEX19-UBR2和TEX19-myosin II复合物调节染色体突触的分子机制。在Specific Aim 2中，我们计划通过遗传和延时成像分析阐明肌动蛋白运动蛋白myosin II和肌动蛋白丝在减数分裂染色体突触和染色体运动中的作用。生物化学，遗传，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见解，这在很大程度上仍未被探索。

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.