MicroRNA biogenesis and specificity in neurotrophin-dependent protein synthesis

描述(由申请人提供)：健康的认知功能取决于对特定靶向基因的正确调控，以响应到来的刺激。脑源性神经营养因子(BDNF)是一种神经营养因子，在神经元的存活、分化和突触可塑性中具有广泛的作用。BDNF可以在转录和翻译水平上调控基因的表达。BDNF的一些功能，包括树突生长和长期突触可塑性，都明确地依赖于BDNF调节蛋白质合成的能力。BDNF通过增强翻译起始因子和延伸因子的活性，从而适度增加神经元的总蛋白质合成，从而全面诱导蛋白质合成机制。然而，BDNF表现出非凡的转录特异性，强烈上调一小部分靶标的翻译，而不影响一些靶标的翻译，下调另一些靶标的翻译。这种惊人的转录本选择性对于BDNF控制神经元蛋白质组成及其作为营养因子的作用至关重要。我们最近描述了一条途径，通过正向和负向调节成熟miRNAs的生物发生来确定特定基因转录产物是被抑制还是经历增强翻译，从而控制蛋白质合成的特异性。这项建议的重点是研究BDNF控制miRNA生物发生的分子机制，这一调控的空间和时间方面，以及这些新的通路组件在认知功能中的作用。我们的研究结果将揭示以前未知的控制基因表达特异性的机制，并为治疗与过程特别相关的大脑疾病提供潜在的新的治疗靶点，如自闭症、脆性X综合征、抑郁症和神经退行性疾病，已知与BDNF和/或翻译失调有关。

DESCRIPTION (provided by applicant): Healthy cognitive function depends upon the correct regulation of specific targeted genes in response to incoming stimuli. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with well-established roles in neuronal survival, differentiation, and synaptic plasticity. BDNF can regulate gene expression at the levels of both transcription and translation. Several functions of BDNF, including dendrite outgrowth and long-term synaptic plasticity, are known to explicitly depend upon the ability of BDNF to regulate protein synthesis. BDNF modestly increases total neuronal protein synthesis by enhancing the activity of translation initiation and elongation factors to globally induce the protein synthesis machinery. However, BDNF demonstrates an extraordinary degree of transcript specificity and strongly upregulates the translation of a small percentage of targets, while leaving some targets unaffected and downregulating the translation of others. This striking transcript selectivity is critical to the control of neuronal protein composition by BDNF and its role as a trophic factor. We recently delineated a pathway by which BDNF controls specificity in protein synthesis through both positively and negatively regulating the biogenesis of mature miRNAs to determine whether specific gene transcripts are repressed or undergo enhanced translation. The focus of this proposal is to examine the molecular mechanisms by which BDNF controls miRNA biogenesis, the spatial and temporal aspects of this regulation, and the role of these novel pathway components in cognitive function. Results from our investigations wil reveal previously unknown mechanisms controlling the specificity of gene expression and offer potential new therapeutic targets for the treatment of brain disorders with particular relevance to processes, such as Autism, Fragile X syndrome, depression, and neurodegenerative disease, with known links to BDNF, dysregulated translation, or both.