Role of first neocortical RNA-operon in specification of neocortical projection n

第一个新皮质 RNA 操纵子在新皮质投射规范中的作用

基本信息

批准号：
8508324
负责人：
Mladen-Roko Rasin
金额：
$ 32.93万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508324
关键词：
Affect Binding Binding Proteins Boxing Cues Data Dendrites Development Disease Eukaryotic Initiation Factors Event Gene Expression Genetic Translation Genome HuR protein Light Mediating Mental disorders Messenger RNA Molecular Molecular Genetics Morphology Myelin P2 Protein Neocortex Neuraxis Neurites Neurodevelopmental Disorder Neurons Operon Pathway interactions Phosphorylation Phosphotransferases Play Post-Transcriptional Regulation Prokaryotic Initiation Factor-2 Protein Binding Protein Biosynthesis Proteins Proteome RNA RNA Splicing RNA-Binding Proteins Regulation Research Role Schizophrenia Signal Transduction Site Specific qualifier value System Thalamic structure Time To specify Translations WNT3 gene Work effective therapy extracellular forkhead protein in vivo insight mRNA Stability member morphogens neocortical nervous system disorder neuropsychiatry novel programs protein expression protein protein interaction response spatiotemporal

项目摘要

DESCRIPTION (provided by applicant): Neocortical neurons show admirable diversity in function, transcriptional programs, dendritic morphology and axonal targets. To specify this remarkable diversity, the intrinsic molecular pathways defining transition from genome to proteome in developing neocortical neurons must be precisely regulated in space and time. RNA- binding proteins (RBPs) are known to be at the cross-road of the genome to proteome axis through the splicing, export, stabilization and translation of transcribed mRNAs. By regulating these post-transcriptional events, RBPs are implicated in control of protein expression levels and neuritogenesis by interfacing with distinct morphogen and/or trophic extracellular signals. Bound mRNAs can include distinct subsets of transcribed mRNAs and form what we call "RNA-operons". These RNA-operons also respond to external cues providing immediate translation to protein, allowing for rapid adjustments of protein levels for a crucial cellular event. These RNA-operons then respond to environmental signals allowing prompt translation of the given mRNA to protein necessary for a particular cellular event. We identified a neocortical RNA-operon that consists of an RBP that binds six neocortical mRNAs characterized by forkhead transcription factor domains at least five days before their translation. To the best of our knowledge this is the first evidence that an RBP binds a subset of six forkhead mRNAs in any system, including developing neocortex. Moreover, we identified a thalamic morphogen signal that affects the phosphorylation state of this neocortical RBP and increases the protein levels of a neocortical forkhead transcription factor. This cascade of events happens before neocortical neurons finish their neurite development. Indeed, both neocortical RBP and thalamic morphogen affect neocortical neuritogenesis. Therefore, our central hypothesis is that this mechanism of thalamic morphogenic regulation of neocortical RNA-operons is crucial for the spatiotemporal specification of subtypes of neocortical neurons and their neurite differentiation. Therefore, we will determine (1) the mechanisms of the neocortical RNA operon in the specification of neocortical projection neurons and their dendrite differentiation; and (2) the role of a thalamic morphogen on neocortical RNA-operon-dependent specifications. To do this, we will use an elegant combination of neuroanatomical, cellular, molecular and genetic approaches. Findings from this proposal will provide previously unrecognized molecular mechanisms of post-transcriptional control in the overall specification of subtypes of neocortical neurons that may open new avenues for treatment of distinct neurodevelopmental disorders.

描述（由申请人提供）：新皮质神经元在功能、转录程序、树突形态和轴突目标方面表现出令人钦佩的多样性。为了明确这种显着的多样性，必须在空间和时间上精确调节发育中的新皮质神经元从基因组到蛋白质组转变的内在分子途径。已知 RNA 结合蛋白 (RBP) 通过转录 mRNA 的剪接、输出、稳定和翻译处于基因组与蛋白质组轴的交叉点。通过调节这些转录后事件，RBP 通过与不同的形态发生素和/或营养细胞外信号相互作用来控制蛋白质表达水平和神经突发生。结合的 mRNA 可以包括转录 mRNA 的不同子集，并形成我们所说的“RNA 操纵子”。这些 RNA 操纵子还对外部信号作出反应，提供立即翻译为蛋白质的能力，从而可以针对关键的细胞事件快速调整蛋白质水平。然后，这些 RNA 操纵子对环境信号做出反应，从而将给定的 mRNA 迅速翻译成特定细胞事件所需的蛋白质。我们鉴定了一种新皮质 RNA 操纵子，它由一个 RBP 组成，该 RBP 至少在翻译前 5 天与 6 个新皮质 mRNA 结合，这些 mRNA 的特征是叉头转录因子结构域。据我们所知，这是第一个证据表明 RBP 在任何系统（包括发育中的新皮质）中与六个叉头 mRNA 的子集结合。此外，我们还发现了丘脑形态发生素信号，该信号影响新皮质 RBP 的磷酸化状态并增加新皮质叉头转录因子的蛋白质水平。这一系列事件发生在新皮质神经元完成神经突发育之前。事实上，新皮质 RBP 和丘脑形态发生素都会影响新皮质神经突发生。因此，我们的中心假设是，丘脑形态发生调节新皮质 RNA 操纵子的这种机制对于新皮质神经元亚型及其神经突分化的时空规范至关重要。因此，我们将确定（1）新皮质RNA操纵子在新皮质投射神经元及其树突分化的规范中的机制； (2) 丘脑形态发生素对新皮质 RNA 操纵子依赖性规范的作用。为此，我们将巧妙地结合神经解剖学、细胞、分子和遗传学方法。该提案的发现将在新皮质神经元亚型的总体规范中提供以前未被认识的转录后控制的分子机制，这可能为治疗不同的神经发育障碍开辟新途径。