Regulation of nuclear migration

核迁移的监管

• 批准号: 6919268
• 负责人: RAHUL WARRIOR
• 金额: $ 28.07万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919268
• 关键词: Drosophilidae; alternatives to animals in research; arthropod genetics; cell component structure /function; cell cycle; cell differentiation; cell growth regulation; cell nucleus; cytoskeleton; developmental genetics; dynein ATPase; embryo /fetus; embryogenesis; genetically modified animals; intermolecular interaction; intracellular transport; oogenesis; protein localization; protein structure function

DESCRIPTION (provided by applicant): The nucleus of the typical eukaryotic cell is located at a defined region and maintained there through active processes. Consequently changes in nuclear position are often highly regulated and play important developmental and cellular roles. Despite the ubiquity of nuclear migration, relatively little is known about the genetics and cell biology of this process in higher eukaryotes. The long-term objective of this research is to determine the mechanisms underlying nuclear migration and to understand its regulation during development, using Drosophila as a model system. Nuclear migration involves an evolutionarily conserved pathway that acts through the microtubule motor cytoplasmic dynein. The Drosophila nudC (DnudC) and Drosophila Lisl (DLisl) genes have important regulatory roles in this process and dynein is essential for movement and anchoring of the oocyte nucleus. We propose to study the mechanism by which dynein function is regulated by genes in the nuclear migration pathway using molecular and biochemical approaches. These studies will provide significant insights into how nuclear migration is regulated in a higher eukaryote and help in understanding how the activity and specificity of dynein, a key microtubule dependent motor can be modulated. Mutations in human LIS1 result in failure of neuronal migration during embryogenesis causing severe mental retardation and premature death. In addition, missense mutations in dynein motor components cause human motor neuron disease and progressive motor neuron degeneration, underscoring the clinical relevance of determining how these ubiquitous motor complexes are regulated. The three specific aims of this proposal are: 1. To investigate the role of DLisl in regulating dynein motor activity: We will examine how DLisl affects dynein function using molecular, genetic and biochemical approaches as well as a sensitive assay that directly measures motor activity in vivo. 2. To determine the biological function of DnudC: We will investigate the role of DnudC, a potential regulator of DLisl and carry out a phenotypic analysis of mutants we have isolated in DnudC. 3. To understand the mechanistic basis of DnudC function: Genetic and structure/function analysis will be used to examine regulatory interactions between DLisl/DnudC and the mechanistic basis of DnudC action.

描述（由申请人提供）：典型真核细胞的核位于定义区域，并通过主动过程维持在那里。因此，核位置的变化通常受到高度调节，并扮演重要的发育和细胞角色。尽管核迁移无处不在，但对高级真核生物中该过程的遗传学和细胞生物学知之甚少。这项研究的长期目标是确定核迁移的机制，并使用果蝇作为模型系统，并了解其在发育过程中的调节。核迁移涉及通过微管运动细胞质动力蛋白作用的进化保守途径。果蝇NUDC（DNUDC）和果蝇（DLISL）基因在此过程中具有重要的调节作用，而动力蛋白对于卵母细胞核的运动和锚定是必不可少的。我们建议研究使用分子和生化方法在核迁移途径中通过基因调节动力蛋白功能的机制。这些研究将提供有关如何在较高真核生物中调节核迁移的重要见解，并有助于了解如何调节动力蛋白的活性和特异性。人LIS1中的突变导致胚胎发生过程中神经元迁移失败，导致严重的智力低下和过早死亡。此外，动力蛋白运动成分的错义突变会导致人类运动神经元疾病和进行性运动神经元变性，强调确定如何调节这些无处不在的运动复合物的临床相关性。该提案的三个具体目的是：1。研究DLISL在调节动力蛋白运动活性中的作用：我们将使用分子，遗传和生化方法以及一种直接测量运动活性在直接测量运动活性的敏感测定法中DLISL如何影响DLISL影响动力蛋白功能。体内。 2。为了确定DNUDC的生物学功能：我们将研究DNUDC的作用，DNUDC是DLISL的潜在调节剂，并对我们在DNUDC中分离的突变体进行了表型分析。 3。了解DNUDC函数的机理基础：遗传和结构/功能分析将用于检查DLISL/DNUDC与DNUDC作用的机理基础之间的调节相互作用。