Control of miRNA-mediated translational repression in neurons

描述（由申请人提供）：突触可塑性与树突状蛋白质合成的调节有关，由此突触刺激激活存储在突触附近的预先存在的mRNA的局部翻译。突触处的局部蛋白质合成可导致突触强度和功效的持久修饰。一个关键的未回答的问题是如何本地化的翻译控制发生。控制的两个特征是明显的;存在翻译的长期和组成性沉默，但也存在翻译的快速和诱导性去沉默。这项资助旨在探索沉默/去沉默背后的机制。我们的工作假设是，这种控制的一部分是由microRNA介导的。这类显著的非编码RNA抑制mRNA转录物的翻译，mRNA转录物在其3'非翻译区含有miRNA结合位点。已知位于树突中的microRNA抑制功能重要的mRNA，并且在某些条件下解抑制。我们的目标是了解miRNAs如何锁定它们的靶mRNA，以及突触活动如何释放它们的靶mRNA进行翻译。为此，我们已经发现，当发生内吞作用时，细胞会释放靶标。内体将被抑制的复合物募集到它们的限制膜，并且随着内体成熟到晚期内体阶段，复合物被解离并翻转。这使得目标能够被释放。该基金的目的是确定在非突触和突触神经元模型中，活性依赖性内吞作用是否从miRNA介导的抑制中释放mRNA。如果我们发现这样的机制，它将促进对突触可塑性的理解。对健康的意义是多方面的。了解调节突触可塑性的分子机制对于破译行为可塑性，精神疾病如何破坏它以及指导新治疗技术的发展至关重要。 公共卫生相关性：microRNA是基因表达的调节因子，它们的功能障碍与各种形式的神经系统疾病有关。该项目旨在了解microRNA如何控制神经元，特别是突触中的蛋白质翻译。它们与突触可塑性的关系特别令人感兴趣。

DESCRIPTION (provided by applicant): Synaptic plasticity has been linked to the regulation of dendritic synthesis of proteins, whereby synaptic stimulation activates local translation of pre-existing mRNAs that are stored close to the synapse. Local protein synthesis at synapses can lead to long-lasting modification in synaptic strength and efficacy. A key unanswered question is how localized translation control occurs. Two features of control are apparent; there is long-term and constitutive silencing of translation but there is also rapid and inducible de-silencing of translation. This grant seeks to explore the mechanisms behind silencing/de-silencing. We are working with the assumption that some of this control is mediated by microRNAs. This remarkable class of non-coding RNAs repress the translation of mRNA transcripts, which contain miRNA-binding sites in their 3' untranslated regions. MicroRNAs located in dendrites are known to repress functionally important mRNAs, and derepress under certain conditions. Our goal is to understand how miRNAs lock up their target mRNAs, and how synaptic activities release their target mRNAs for translation. To this end, we have discovered that cells release targets when endocytosis occurs. Endosomes recruit repressed complexes to their limiting membranes, and as endosomes mature to late endosome stages, complexes are dissociated and turned over. This enables targets to be released. The aims of the grant are to determine if activity-dependent endocytosis releases mRNAs from miRNA-mediated repression in a non-synaptic and synaptic neuronal model. If we uncover such a mechanism, it would advance understanding of synaptic plasticity. The significance to health is manifold. Understanding the molecular mechanisms that regulate synaptic plasticity is of paramount importance to decipher behavioral plasticity, how mental illness can disrupt it, and guide development of new therapeutic technologies. PUBLIC HEALTH RELEVANCE: MicroRNAs are regulators of gene expression, and their dysfunction is linked to diverse forms of neurological disorders. This project is to understand how microRNAs control protein translation in neurons, particularly in synapses. Their relationship to synaptic plasticity is of particular interest.