NEURON SPECIFIC FUNCTIONS OF CYTOPLASMIC DYNEIN

描述(由申请人提供)：本计划的长期目标是了解 使细胞质动力蛋白在神经元中执行各种但独立控制的功能的机制，包括逆行和缓慢的顺行轴突运输，并了解依赖动力蛋白的神经元在发育过程中核迁移的意义。细胞质动力蛋白的功能特异性被归因于运动复合体亚单位组成的变化以及招募运动到特定运输任务的辅助多肽。这项建议利用果蝇强大的分子生物学、遗传学和转基因技术来验证这一假说。具体地说，拟议的实验通过分析动力蛋白中间链的各种异构体的亚细胞定位，以及确定缺乏特定异构体的动物是否在神经元功能和发育方面表现出缺陷，来评估动力蛋白中间链的各种异构体的功能特异性。为了确定哪些其他分子可能与神经元中的动力蛋白专一性有关，我们建议进行实验，比较一系列与动力蛋白功能有关的突变体对神经元专一性运输的影响。 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。果蝇眼部光感受器的核团 典型的依赖动力蛋白的核迁移，最终导致每类光感受器的特定核定位。精确的核定位的生物学意义尚不清楚。新出现的微阵列技术将被用来在全基因组的基础上分析细胞核正常定位和错位的眼睛在转录方面的差异。对果蝇眼睛中信号转导和基因表达之间相互作用的广泛了解将有助于分析所观察到的任何差异。运动功能异常与大脑发育异常以及神经和神经退行性疾病有关，包括Miller-Dieker无脑畸形、精神分裂症、 Charcot-Marie-Tooth病2A型，人类运动神经元病，视网膜色素变性，以及 阿尔茨海默氏症。

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.