Role of Micro-RNAs in Neuronal Circuit Formation and Function

Micro-RNA 在神经元回路形成和功能中的作用

基本信息

批准号：
7586285
负责人：
Erik M Ullian
金额：
$ 20.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586285
关键词：
Accounting Adenylate Cyclase Affect Animal Model Area Attention Deficit Disorder Autistic Disorder Behavior Disorders Behavioral Biogenesis Biological Models Biology Brain Cell physiology Cellular biology Complement DNA Data Defect Dendrites Dendritic Spines Development DiGeorge Syndrome Disease Enzymes Excision FMRP Foundations Fragile X Syndrome Functional RNA Gene Targeting Genes Genetic Gifts Goals Golgi Apparatus Hippocampus (Brain)Human Human Genome Individual Investigation Junk DNA Knock-out Knockout Mice Lead Learning Life Link Live Birth Mammals Memory Mental disorders MicroRNAs Molecular Morphology Mus Mutant Strains Mice Nervous system structure Neuraxis Neurites Neurons Nucleotides Pathway interactions Phenotype Play Population Prevalence Process Proteins Psyche structure Regulatory Pathway Research Research Personnel Role Schizophrenia Signal Pathway Small RNA Sorting - Cell Movement Staging Synapses Synaptic Transmission Testing Translating Translational Regulation Translational Repression Vertebral column Work gastrulation hippocampal pyramidal neuron human DICER1 protein in vivo link protein mouse model neuron development neuronal survival public health relevance recombinase synaptic function synaptotagmin VI tool

项目摘要

DESCRIPTION (provided by applicant): Nearly 90% of the human genome is composed of non-coding regions that are not translated into proteins. Previously referred to as "junk" DNA it has recently become apparent that some of this DNA is used to make small app. 22-nucleotide single stranded RNAs known as micro-RNAs (miRNAs). Within the last several years researchers have discovered that these miRNAs are not only important for a variety of processes, but essential. Indeed, removing miRNAs early in development by knocking out the key RNAseIII enzyme required for their synthesis, Dicer, is lethal at the very early stages of gastrulation. Importantly, these miRNAs are continuously expressed throughout the life of mammals and it is clear that they continue to play important regulatory roles in cellular function. The greatest variety of miRNAs are expressed in the nervous system, including the cortex, making it paramount to understand what role the miRNAs play in normal cortical function and mental and behavioral disorders. To date only a few miRNAs has been investigated in hippocampal neurons in culture and these miRNA was found to be required for proper neurite outgrowth and synapse morphology. Importantly computational analyses of likely targets indicate numerous signaling pathways that impact neuronal survival and function are regulated by miRNAs. We propose to use the power of mouse genetics to specifically remove all miRNAs from pyramidal cortical neurons after they have differentiated using a conditional knock out of Dicer and another key gene for the miRNA pathway DGCR8 and then ask what role miRNAs play in dendrite morphology, synaptic spines, and function. Finally, we will identify the complement of miRNAs that are expressed in purified pyramidal neurons that may underlie the observed phenotypes. These data will provide the first inroad to understanding the role of small RNA biology in normal brain function and disease. These initial studies will allow us to develop and perfect the tools to extend these studies to other, layer specific, pyramidal neurons in the cortex and to specific miRNAs that we have identified as candidates for impacting synaptic transmission or affecting schizophrenia-linked genes. PUBLIC HEALTH RELEVANCE. The small RNA pathway is a poorly understood, but essential translational repression pathway heavily expressed in mammalian neurons. This pathway is likely to be important for normal neuronal function and is almost certainly affected in a variety of behavioral and mental disorders such as autism and schizophrenia. These studies will be among the first to provide a detailed cellular and molecular description of the small RNA pathways in normal neuronal development and function in vivo.

描述（由申请人提供）：近 90% 的人类基因组由不翻译成蛋白质的非编码区组成。以前被称为“垃圾”DNA，最近发现其中一些 DNA 被用来制作小型应用程序。 22 核苷酸单链 RNA 称为 micro-RNA (miRNA)。在过去的几年里，研究人员发现这些 miRNA 不仅对多种过程很重要，而且是必需的。事实上，通过敲除合成所需的关键 RNAseIII 酶 Dicer，在发育早期去除 miRNA，在原肠胚形成的早期阶段是致命的。重要的是，这些 miRNA 在哺乳动物的整个生命周期中持续表达，并且很明显它们在细胞功能中继续发挥重要的调节作用。种类最多的 miRNA 在神经系统（包括皮质）中表达，因此了解 miRNA 在正常皮质功能以及精神和行为障碍中发挥的作用至关重要。迄今为止，仅在培养的海马神经元中研究了少数 miRNA，并且发现这些 miRNA 是适当的神经突生长和突触形态所必需的。重要的是，对可能靶标的计算分析表明，影响神经元存活和功能的众多信号通路均受到 miRNA 的调节。我们建议利用小鼠遗传学的力量，通过条件性敲除 Dicer 和 miRNA 途径 DGCR8 的另一个关键基因，在锥体皮质神经元分化后特异性去除所有 miRNA，然后探究 miRNA 在树突形态、突触中发挥什么作用。脊柱和功能。最后，我们将鉴定在纯化的锥体神经元中表达的 miRNA 的补充，这些 miRNA 可能是观察到的表型的基础。这些数据将为理解小 RNA 生物学在正常大脑功能和疾病中的作用提供第一步。这些初步研究将使我们能够开发和完善工具，将这些研究扩展到皮层中的其他层特异性锥体神经元，以及我们已确定为影响突触传递或影响精神分裂症相关基因的候选者的特定 miRNA。公共卫生相关性。小RNA途径是一种人们知之甚少但重要的翻译抑制途径，在哺乳动物神经元中大量表达。该通路可能对正常神经元功能很重要，并且几乎肯定会受到自闭症和精神分裂症等各种行为和精神疾病的影响。这些研究将是首批对体内正常神经元发育和功能中的小 RNA 通路提供详细的细胞和分子描述的研究之一。