Role of first neocortical RNA-Operon in specification of neocortical projection neurons

第一个新皮质 RNA 操纵子在新皮质投射神经元规范中的作用

基本信息

批准号：
9384000
负责人：
Mladen-Roko Rasin
金额：
$ 33.95万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9384000
关键词：
Affect Autistic Disorder Automobile Driving Axon Behavior Binding Complex Coupled Data Dendrites Development Disease ELAV protein Epilepsy Event Funding Gene Expression Genes Genetic Translation Glutamates Goals Grant Human In Vitro Individual Knowledge Light Mediating Messenger RNA Molecular Molecular Genetics Morphology Mutate Neocortex Neurites Neurodevelopmental Disorder Neurons Neurosciences Oligodendroglia Operon Pathology Plasticizers Polyribosomes Post-Transcriptional Regulation Process Protein Biosynthesis Proteins Public Health Publishing RNA RNA-Binding Proteins Regulation Reporting Research Ribosomal Proteins Ribosomes Role Shapes Signal Transduction Specificity Testing Thalamic structure Therapeutic Time Transcriptional Regulation Transgenic Mice Translations Tyrosine Kinase Domain WNT Signaling Pathway WNT3 gene Work cell type combinatorial developmental plasticity experimental study gain of function genetic approach in vivo innovation laser capture microdissection morphogens neocortical nervous system disorder neurodevelopment neurogenesis neuron development neuropsychiatric disorder novel postnatal prenatal prevent receptor response spatiotemporal transcription factor

项目摘要

Abstract: The long-term goal of this competing renewal is to understand how the previously underappreciated regulation of protein synthesis (mRNA translation) in space and time drives neuronal diversity. Neuronal diversity relies on intricate steps of functional gene expression. It has been established that spatio-temporal expression of transcription factors drive neuronal and dendritic differences. While unidentified molecular mechanisms of post- transcriptional control like mRNA translation have strong potential to drive neuronal diversity, they have been thus far understudied. mRNA translation is the final essential step in the functional gene expression. We showed in the previous funding period that regulation of this process is of the key molecular mechanisms in neocortical neuronal development. Our published and preliminary studies, supported by this grant, have led to five important discoveries. First, we described that genes associated with mRNA translation show temporal dynamics in both expression and activity during neurogenesis in developing neocortices. Second, we reported that mRNA translation and the core components of the ribosome in the neocortex – the “neocortical ribosome signature”– are developmentally regulated by the intrinsic Elav RNA binding proteins (RBPs). Third, we published that timed ingrowth of thalamocortical axons secrete WNT morphogen and extrinsically define temporally dynamic mRNA translation and the ribosome signature in the developing neocortex. Fourth, that both Elav RBPs and thalamocortical WNT signaling dictate identities of developing neocortical glutamatergic neurons and maturation of oligodendrocytes. Finally, we reported that prenatal deletion of an Elav RBP results in abnormal neocortical dendritogenesis and behavior. However, there are still critical gaps in our knowledge regarding how timed mRNA translation and ribosome signature dictate development of distinct neocortical glutamatergic neurons. In this proposal, we hypothesize that layer-specific ribosome signatures and RBPs dictate timed mRNA translation in distinct subpopulations of developing glutamatergic neurons, thus governing their neurite development. Therefore, we will determine (1) how RBP-defined ribosome signatures dictate mRNA translation specificity and dendrite and axon development within distinct layer specific subpopulations of neocortical glutamatergic neurons; and (2) how WNT-mediated Frizzled signaling dictates RBP-defined assembly of the neocortical layer- specific ribosome signature, mRNA translation and dendrite and axon development in distinct glutamatergic neurons. To do this, we will use an elegant combination of neuroanatomical, cellular, molecular, and genetic approaches. We have produced all of the preliminary data necessary to demonstrate feasibility of the proposed approaches. Findings from this proposal will reveal previously unrecognized molecular mechanisms of post- transcriptional control in the overall specification of neocortical glutamatergic neurons and dendrite development, which can open new avenues for treatment of neurological and neuropsychiatric disorders involving these.

抽象的：这种竞争性更新的长期目标是了解以前被低估的监管如何空间和时间上的蛋白质合成（mRNA 翻译）驱动神经元多样性。功能基因表达的复杂步骤已经确定。转录因子驱动神经和树突差异，而后的分子机制尚未确定。像 mRNA 翻译这样的转录控制具有驱动神经多样性的强大潜力，它们已被迄今为止，我们还没有充分研究 mRNA 翻译是功能性基因表达的最后一个重要步骤。在之前的资助期间，该过程的调节是新皮质的关键分子机制在这笔资金的支持下，我们已发表的初步研究取得了五项重要成果。首先，我们描述了与 mRNA 翻译相关的基因在两者中都显示出时间动态。其次，我们报道了 mRNA 在发育中的新皮质神经发生过程中的表达和活性。翻译和新皮质核糖体的核心成分——“新皮质核糖体特征”—— 第三，我们发布了这个时间点。丘脑皮质轴突的向内生长分泌 WNT 形态发生素并从外部定义时间动态 mRNA 第四，Elav RBP 和发育中的新皮质中的翻译和核糖体特征。丘脑皮质 WNT 信号传导决定新皮质谷氨酸能神经元的发育和成熟最后，我们报道了 Elav RBP 的产前缺失会导致新皮质异常。然而，我们对于 mRNA 的时间控制仍存在重大差距。翻译和核糖体特征决定了不同新皮质谷氨酸能神经元的发育。建议，我们认为层特异性核糖体特征和 RBP 决定了 mRNA 的定时翻译发育中的谷氨酸能神经元的不同亚群，从而控制它们的神经突发育。因此，我们将确定 (1) RBP 定义的核糖体特征如何决定 mRNA 翻译特异性，以及新皮质谷氨酸能的不同层特定亚群内的树突和轴突发育神经元；以及（2）WNT 介导的卷曲信号如何决定 RBP 定义的新皮质层组装 - 不同谷氨酸能细胞中的特定核糖体特征、mRNA 翻译以及树突和轴突发育为此，我们将巧妙地结合神经解剖学、细胞、分子和遗传。我们已经提供了证明所提议的可行性所需的所有初步数据。该提案的研究结果将揭示以前未认识到的后遗症的分子机制。新皮质谷氨酸能神经元和树突发育总体规范的转录控制，这可以为治疗涉及这些的神经系统和神经精神疾病开辟新途径。