NEURON SPECIFIC FUNCTIONS OF CYTOPLASMIC DYNEIN

描述（由申请人提供）：本提案的长期目标是了解 这些机制允许细胞质动力蛋白在神经元中执行不同但独立控制的功能，包括逆行和缓慢的顺行轴突运输，并了解发育过程中动力蛋白依赖的神经元核迁移的意义。细胞质动力蛋白的功能特异性归因于运动复合体亚基组成的变化和辅助多肽，这些多肽将运动复合体招募到某些运输任务中。这项提议利用果蝇强大的分子生物学、遗传学和转基因技术来检验这一假设。具体而言，所提出的实验通过分析其亚细胞定位以及确定缺乏特定同种型的动物是否表现出神经元功能和发育缺陷来评估动力蛋白中间链的各种同种型的功能特异性。为了确定哪些其他分子可能有助于神经元中的动力蛋白特异性，提出了实验来比较与动力蛋白功能有关的突变体对神经元特异性转运的影响 流程.动力蛋白转运的一个重要作用是定位和组织亚细胞 成分，包括原子核。果蝇眼睛的光感受器的细胞核 刻板的，动力蛋白依赖的核迁移，最终在特定的核定位为每一类感光细胞。精确核定位的生物学意义尚不清楚。新兴的微阵列技术将被用来在全基因组的基础上，在正常定位和错位核的眼睛转录的差异。关于果蝇眼睛中信号转导和基因表达之间相互作用的广泛知识将有助于分析任何观察到的差异。异常的运动功能与异常的大脑发育以及神经和神经退行性疾病有关，包括米勒-迪克尔无脑畸形、精神分裂症、 腓骨肌萎缩症2A型，人运动神经元病，视网膜色素变性，和 老年痴呆症

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to understand the mechanisms that allow cytoplasmic dynein to perform diverse, yet independently controlled functions in neurons, including retrograde and slow anterograde axonal transport, and to understand the significance of dynein-dependent neuronal nuclear migration during development. Functional specificity of cytoplasmic dynein has been attributed to variation in subunit composition of motor complexes and to accessory polypeptides that recruit the motor to certain transport tasks. This proposal tests this hypothesis using the powerful molecular biology, genetics and transgenic techniques of Drosophila. Specifically, the proposed experiments assess the functional specificity of various isoforms of the dynein intermediate chain by analyzing their subcellular localization, as well as determining whether animals that lack specific isoforms exhibit defects in neuronal function and development. To define which other molecules might contribute to dynein specificity in neurons, experiments are proposed to compare the effect of a collection of mutants implicated in dynein function on neuron-specific transport processes. An important role of dynein-based transport is positioning and organizing subcellular components, including nuclei. The nuclei of the photoreceptors of the Drosophila eye undergo stereotypic, dynein-dependent nuclear migrations that culminate in specific nuclear positioning for each class of photoreceptor. The biological significance of the precise nuclear positioning is unknown. The emergent microarray technology will be utilized to profile differences in transcription on a genome-wide basis in eyes with normally localized and with mispositioned nuclei. The extensive knowledge about the interplay between signal transduction and gene expression in the Drosophila eye will facilitate analyzing any observed differences. Aberrant motor function has been linked to anomalous brain development and neurological and neurodegenerative diseases, including Miller-Dieker lissencephaly, schizophrenia, Charcot-Marie-Tooth Disease Type 2A, human motor neuron disease, retinitis pigmentosa, and Alzheimer's disease.