Mechanism of RNA Localization in Drosophila Development

 描述（由申请人提供）：信使RNA定位在产生细胞和发育极性所需的蛋白质的不对称分布中起关键作用。mRNA定位途径的损伤与人类疾病如脊髓性肌萎缩症和脆性X综合征有关，mRNA靶向癌细胞突起表明在转移中的作用。将特定的mRNA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（RNP）的组装和运输。如何赋予这个过程的特异性，特别是在许多mRNA同时定位的细胞中，还知之甚少。该提案整合了生物化学，遗传学，定量和基于实时成像的方法来研究不同的mRNA如何被特异性识别以形成定位能力RNP并组装成更高阶的功能性RNA颗粒。目的1和2解决了许多转录本在果蝇卵母细胞后部的生殖质的末端定位及其生殖细胞祖细胞的差异遗传。该系统提供了一个理想的机会，调查的分子机制，调节的形成，组成和行为的RNP的本地化和功能，在产生不对称性必不可少的。目的3利用我们最近在果蝇感觉神经元树突中鉴定出的大量局部RNA。这一目标的主要目标是严格评估RNA定位在神经元中的功能意义，并探讨目标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.