Mechanism of RNA Localization in Drosophila Development

 描述(由申请人提供)：信使RNA定位在创造细胞和发育极性所必需的蛋白质的不对称分布方面起着关键作用。在人类疾病中，如脊髓性肌萎缩症和脆性X综合征都涉及到信使核糖核酸定位通路的损伤，而靶向癌细胞突起的信使核糖核酸在肿瘤转移中起着重要作用。将特定的mRNAs分选到不同的亚细胞结构域是一个复杂的过程，涉及核糖核蛋白颗粒(RNPs)的组装和运输。这一过程的特异性是如何被赋予的，特别是在许多mRNA同时定位的细胞中，人们知之甚少。这一建议结合了生化、遗传、定量和实时成像的方法，以研究不同的mRNAs是如何被特异性识别以形成具有定位能力的RNPs并组装成更高顺序的功能RNA颗粒的。目标1和2解决了果蝇卵母细胞后部种质中大量转录本的末端集体定位以及生殖细胞前体对它们的差异遗传。这个系统提供了一个理想的机会来研究调控RNPs的形成、组成和行为的分子机制，这些RNPs对于定位和产生不对称的功能是必不可少的。目的3利用我们最近在果蝇感觉神经元树突中发现的大量定位RNA。这一目标的主要目的是批判性地评估神经元中RNA定位的功能意义，并探索目标1和2中出现的机制原理的普遍性。

 DESCRIPTION (provided by applicant): Messenger RNA localization plays a key role in creating the asymmetric distributions of proteins necessary for cellular and developmental polarity. Impairment of mRNA localization pathways has been implicated in human diseases such as spinal muscular atrophy and fragile X syndrome and targeting of mRNAs to cancer cell protrusions suggests a role in metastasis. The sorting of specific mRNAs to different subcellular domains is a complex process involving the assembly and trafficking of ribonucleoprotein particles (RNPs). How specificity is conferred on this process, particularly in cells where many mRNAs are localized concurrently, is poorly understood. This proposal integrates biochemical, genetic, and quantitative and live imaging-based approaches to investigate how different mRNAs are specifically recognized to form localization competent RNPs and assembled into higher order, functional RNA granules. Aims 1 and 2 address the end masse localization of numerous transcripts to the germ plasm at the posterior of the Drosophila oocyte and their differential inheritance by germ cell progenitors. This system affords an ideal opportunity to investigate the molecular mechanisms that regulate the formation, composition, and behavior of RNPs essential for localization and function in generating asymmetry. Aim 3 capitalizes on our recent identification of a large number of localized RNAs in Drosophila sensory neuron dendrites. The major goals of this aim are to critically assess the functional significance of RNA localization in neurons and to probe the generality of the mechanistic principles emerging from Aims 1 and 2.