Translational Control in Neurons

修订摘要：描述（由申请人提供）： 突触的长期可塑性变化需要重新合成蛋白质。这一要求的一部分，它建议，是满足翻译的mRNA定位于突触后微域。根据这个模型，本地翻译提供了空间和时间特异性，这是必要的输入依赖性调制的突触蛋白库。这一概念的核心要求是在翻译水平上控制基因表达。特别是，为了提供时空特异性，神经元中的翻译机制必须受到严格控制，使得蛋白质合成仅在正确的地点和正确的时间才能实现。这种翻译控制的功能机制是什么，它们是如何调节的？在这里提出的研究项目中，假设小RNA在神经元的翻译控制机制中起着重要作用。具体而言，它是证实，不可翻译的树突状BC 1 RNA作为一个阻遏物的翻译起始途径。为了验证这一假设，我们将剖析BC 1介导的翻译抑制机制的结构-功能关系。该分析将针对BC 1结构域结构的功能相关性，以及BC 1 RNA在翻译起始途径中的功能靶标。BC 1介导的阻遏也将在活细胞中功能性地确定，使用模型系统，如非洲爪蟾卵母细胞。本研究的总体目标是阐明小分子神经元RNA介导的局部翻译调控的机制和功能意义。

REVISED ABSTRACT: DESCRIPTION (provided by applicant): Long-term plastic changes at the synapse require de novo synthesis of proteins. Part of this requirement, it is suggested, is met by translation in situ of mRNAs that are localized to postsynaptic microdomains. Local translation, according to this model, provides the spatial and temporal specificity that is necessary for input-dependent modulations of synaptic protein repertoires. A central requisite for this concept is the control of gene expression at the level of translation. In particular, to afford spatio-temporal specificity, translational machinery in neurons will have to be tightly controlled such that protein synthesis is enabled only at the right place and at the right time. What are the functional mechanisms of such translational control, and how are they regulated? In the research project proposed here, it is hypothesized that small RNAs play an instrumental role in translational control mechanisms in neurons. Specifically, it is conjectured that non-translatable dendritic BC1 RNA operates as a repressor in the translation initiation pathway. To test this hypothesis, we will dissect structure-function relationships that are underlying BC1-mediated translational repression mechanisms. The analysis will be directed at the functional relevance of the BC1 domain architecture, and at the functional targets of BC1 RNA in the translation initiation pathway. BC1-mediated repression will also be functionally ascertained in living cells, using model systems such as Xenopus oocytes. It is the overall goal of the proposed research to elucidate mechanisms and functional significance of local translational control mediated by small neuronal RNAs.