The Control of Neuronal Diversity and Plasticity by the let-7-C microRNA Pathway

描述（由申请人提供）：该申请概述了一项基础研究计划，该计划利用果蝇模式生物来阐明控制神经可塑性的基本分子机制。神经可塑性是神经系统的一个普遍特征，它解释了成年人的大脑如何随着时间的推移而变化，并对异质的外部刺激做出反应，包括激素，营养，日光和经验。神经可塑性的缺陷与多种精神障碍有关，包括抑郁症、双相情感障碍和精神分裂症。了解控制神经可塑性的分子机制将导致旨在治疗和治愈这些和其他精神疾病的治疗干预。本申请的中心假设是let- 7-复合体microRNA（miRNA）途径是成年期以及发育期间神经可塑性的主要调节因子。miRNAs是近年来发现的一类调控靶基因表达的调控RNA，let-7复合体编码三种高度保守的共转录的神经miRNAs，分别为miR-100、let-7和miR-125。尽管许多miRNA在成人大脑中表达，但目前还没有已知的体内脑功能所需的miRNA的例子。基于我们新的初步数据，我提出let-7- Complex miRNA通路至少调节神经可塑性的三个方面：突触可塑性、神经干细胞可塑性和轴树突重塑。此外，我提出let-7- Complex miRNA途径以相同的方式调节这些过程中的每一个，通过转录后调节神经元形态的一小组剂量敏感性转录因子的表达。为了测试这个模型，我将全面描述果蝇let-7-Complex miRNA通路的分子、细胞和行为功能，如下所示：1）确定let- 7-Complex miRNAs在蝇蕈体中的发育和发育后功能，2）关联let-7-Complex miRNAs的分子、细胞和行为需求，和3）鉴定调节let-7-复合体miRNAs的表达或活性的因子是否也调节神经可塑性。通过阐明在神经元生命的多个阶段控制可塑性的高度保守机制，该项目将能够设计调节神经可塑性的分子疗法，从而治疗多种精神疾病。精神疾病如压力、抑郁、自闭症、躁郁症和精神分裂症都与神经可塑性缺陷有关。在这份资助申请中，我描述了一些实验，这些实验旨在确定控制果蝇神经可塑性的潜在机制，果蝇是一种遗传上易于处理的模式生物。该机制是let-7-Complex microRNA对特定剂量敏感性转录因子的转录后调节。考虑到let-7-Complex microRNA的保守性，它们的靶点，以及它们从果蝇到人类的神经表达谱，我预计这项工作将阐明一个控制人类神经可塑性多个方面的基本表观遗传途径，从而广泛影响精神疾病的治疗。

DESCRIPTION (provided by applicant): This application outlines a basic research plan that utilizes the fruit fly model organism to illuminate a fundamental molecular mechanism controlling neuroplasticity. Neuroplasticity is a general feature of the nervous system and explains how the adult brain changes over time and in response to heterogeneous external stimuli, including hormones, nutrition, daylight and experience. Defects in neuroplasticity have been associated with multiple mental disorders, including depression, bipolar disorder, and schizophrenia. Understanding the molecular mechanisms controlling neuroplasticity will lead to therapeutic interventions designed to treat and cure these and other mental illnesses. The central hypothesis of this application is that the let- 7-Complex microRNA (miRNA) pathway is a major regulator of neuroplasticity during adulthood as well as development. MiRNAs are a recently discovered class of regulatory RNAs that control the expression of target genes and the let-7-Complex encodes three highly conserved and co-transcribed neural miRNAs, miR-100, let-7 and miR-125. Although many miRNAs are expressed in the adult human brain, there are currently no known examples of miRNAs that are required for brain function in vivo. Based on our novel preliminary data, I propose that the let-7- Complex miRNA pathway regulates at least three aspects of neuroplasticity: synaptic plasticity, neural stem cell plasticity, and axodendritic remodeling. Furthermore, I propose that the let-7- Complex miRNA pathway regulates each of these processes in the same way, by post- transcriptionally modulating the expression of a small group of dosage-sensitive transcription factors that regulate neuronal morphology. To test this model, I will comprehensively characterize the molecular, cellular and behavioral function of let-7-Complex miRNA pathway in the fruit fly, as follows: 1) determine the developmental and post-developmental function of let- 7-Complex miRNAs in the fly mushroom body, 2) relate the molecular, cellular and behavioral requirements of let-7-Complex miRNAs, and 3) identify whether factors that regulate the expression or activity of let-7-Complex miRNAs also modulate neuroplasticity. By illuminating a highly conserved mechanism that controls plasticity during multiple phases of a neuron's life, this project will enable the design of molecular therapies that adjust neuroplasticity and thereby treat multiple mental disorders. Mental illnesses like stress, depression, autism, bipolar disorder and schizophrenia have all been associated with defects in neuroplasticity. In this grant application, I describe experiments designed to identify an underlying mechanism controlling neuroplasticity in the fruit fly, which is a genetically tractable model organism. This mechanism is the post-transcriptional regulation of specific dosage-sensitive transcription factors by let-7-Complex microRNAs. Given the conservation of the let-7-Complex microRNAs, their targets, and their neural expression profiles from flies to humans, I anticipate that this work will illuminate a fundamental epigenetic pathway controlling multiple aspects of neuroplasticity in humans and thereby broadly impact the treatment of mental illness.