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：
10204116
负责人：
Mladen-Roko Rasin
金额：
$ 33.85万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204116
关键词：
Affect 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 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 autism spectrum disorder axonal pathfinding 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：这种竞争更新的长期目标是了解以前未被低估的法规空间和时间中蛋白质合成（mRNA翻译）的驱动神经元多样性。神经元的多样性依赖功能基因表达的复杂步骤。已经确定了转录因子驱动神经元和树突差异。而后未鉴定的分子机制转录控制（例如mRNA翻译）具有驱动神经元多样性的强大潜力，它们一直是到目前为止理解。 mRNA翻译是功能基因表达的最后一步。我们展示了在上一个资金期间，该过程的调节是新皮质的关键分子机制神经元发展。我们已发表和初步的研究得到了这笔赠款的支持，导致了五个重要的发现。首先，我们描述了与mRNA翻译相关的基因在两者中都显示出临时动力学在发展新皮层中神经发生过程中的表达和活性。其次，我们报道了mRNA 新皮层中核糖体的翻译和核心成分 - “新皮层核糖体特征” - 由固有的ELAV RNA结合蛋白（RBP）开发。第三，我们发表了这个时机丘脑皮质轴突的向内分泌Wnt形态学，外在定义暂时动态mRNA 发展新皮层中的翻译和核糖体特征。第四，埃拉夫RBP和丘脑皮质Wnt信号指示发展新皮质谷氨酸能神经元和成熟的身份少突胶质细胞。最后，我们报道了ELAV RBP的产前缺失会导致新皮质的异常树突生成和行为。但是，我们关于如何定时mRNA仍然存在关键的差距翻译和核糖体签名决定了不同的新皮质谷氨酸能神经元的发展。在这个提案，我们假设该层特异性核糖体特征和RBP决定了定时mRNA翻译发展谷氨酸能神经元的独特亚群，从而管理其神经元的发育。因此，我们将确定（1）RBP定义的核糖体特异性和新皮质谷氨酸能的不同层特有亚群体内的树突和轴突发育神经元；（2）Wnt介导的毛躁信号传导如何决定新皮层层的RBP定义的组装特定的核糖体签名，mRNA翻译以及树突和轴突发育在不同的谷氨酸能神经元。为此，我们将使用神经解剖学，细胞，分子和遗传的优雅组合方法。我们制作了所有必要的初步数据，以证明所提出的可行性方法。该提案的发现将揭示以前未识别的后分子机制新皮质谷氨酸能神经元和树突发育的总体规范中的转录控制，这可以为治疗涉及这些疾病的神经和神经精神疾病的治疗开放新途径。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein Synthesis in the Developing Neocortex at Near-Atomic Resolution Reveals Ebp1-Mediated Neuronal Proteostasis at the 60S Tunnel Exit.

DOI：
10.1016/j.molcel.2020.11.037
发表时间：
2021-01-21
期刊：
Molecular cell
影响因子：
16
作者：
Kraushar ML;Krupp F;Harnett D;Turko P;Ambrozkiewicz MC;Sprink T;Imami K;Günnigmann M;Zinnall U;Vieira-Vieira CH;Schaub T;Münster-Wandowski A;Bürger J;Borisova E;Yamamoto H;Rasin MR;Ohler U;Beule D;Mielke T;Tarabykin V;Landthaler M;Kramer G;Vida I;Selbach M;Spahn CMT
通讯作者：
Spahn CMT

Adult Upper Cortical Layer Specific Transcription Factor CUX2 Is Expressed in Transient Subplate and Marginal Zone Neurons of the Developing Human Brain.