Regulation of nuclear migration

核迁移的监管

• 批准号: 7267591
• 负责人: RAHUL WARRIOR
• 金额: $ 26.5万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267591
• 关键词: Affect; Amino Acids; Animals; Biochemical; Biological Assay; Biological Models; Biological Phenomena; Biological Process; Brain; Brush Border; Cell Nucleus; Cell division; Cell physiology; Cells; Cellular biology; Cessation of life; Clinical; Complex; Condition; Congenital Abnormality; Development; Disruption; Drosophila genus; Dynein ATPase; Embryo; Embryonic Development; Endocrine; Epilepsy; Eukaryota; Eukaryotic Cell; Failure; Female; Fertilization; Genes; Genetic; Genetic Structures; Glues; Human; Immigration; Inherited; Intestines; Measures; Medical; Mental Retardation; Microtubules; Missense Mutation; Molecular; Molecular Genetics; Motor; Motor Activity; Motor Neuron Disease; Movement; Mus; Muscle Fibers; Mutation; Neurons; Nuclear; Oocytes; Organism; Pathway interactions; Phylogenetic Analysis; Play; Positioning Attribute; Process; Proteins; Regulation; Regulatory Pathway; Research; Research Personnel; Role; Specificity; Vertebrates; Work; Yeasts; antibody inhibitor; base; cell type; clinically relevant; dynactin; in vivo; insight; male; migration; motor neuron degeneration; mutant; programs

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(申请人提供)：典型的真核细胞的核位于一个确定的区域，并通过活跃的过程保持在那里。因此，核位置的变化通常是高度调控的，并发挥着重要的发育和细胞作用。尽管核迁移无处不在，但人们对高等真核生物核迁移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以果蝇为模型系统，确定核迁移的潜在机制，并了解其在发育过程中的调控。核迁移涉及一条进化上保守的途径，该途径通过微管运动胞浆动力蛋白起作用。果蝇nudC基因(DnudC)和Drisl基因在这一过程中起着重要的调节作用，动力蛋白对卵母细胞核的移动和锚定是必不可少的。我们建议用分子和生物化学的方法来研究核迁移途径中的基因调控动力蛋白功能的机制。这些研究将为在高等真核生物中如何调控核迁移提供重要的见解，并有助于理解如何调节动力蛋白的活性和特异性，动力蛋白是一种关键的微管依赖运动。人类Lis1基因突变导致胚胎发育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，动力蛋白运动组件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退化，这突显了确定这些无处不在的运动复合体是如何受到调控的临床相关性。这项建议的三个具体目的是：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体内运动活性的灵敏方法来研究DLISL如何影响动力蛋白功能。2.为了确定DnudC的生物学功能：我们将研究DnudC的作用，并对我们从DnudC中分离到的突变株进行表型分析。3.了解DnudC功能的机制基础：将通过遗传和结构/功能分析来研究DLIS1/DnudC与DnudC作用的机制基础之间的调节相互作用。