Translational Control in Neurons

修订摘要：说明(申请人提供)： 突触的长期可塑性变化需要蛋白质的从头合成。这一要求的一部分，被认为是通过定位于突触后微域的mRNAs的原位翻译来满足的。根据这一模型，局部翻译提供了突触蛋白质谱依赖于输入的调制所必需的空间和时间特异性。这一概念的一个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得到严格控制，以便只有在正确的地点和正确的时间才能合成蛋白质。这种翻译控制的作用机制是什么？它们是如何被调控的？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发挥重要作用。具体地说，推测不可翻译的树突状BC1RNA在翻译起始途径中起抑制作用。为了验证这一假设，我们将剖析bc1介导的翻译抑制机制背后的结构-功能关系。分析将针对BC1域结构的功能相关性，以及BC1RNA在翻译起始途径中的功能靶点。使用非洲爪哇卵母细胞等模型系统，也将在活细胞中从功能上确定bc1介导的抑制。阐明小神经元RNA介导的局部翻译控制的机制和功能意义是本研究的总体目标。

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.