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，树突形态和轴突靶标方面表现出令人钦佩的多样性。为了指定这种显着的多样性，在开发新皮层神经元中定义从基因组到蛋白质组过渡的内在分子途径必须在时空和时间上得到精确调节。已知RNA结合蛋白（RBP）通过剪接，导出，稳定和转录mRNA的剪接，导出，稳定和翻译已知在基因组的交叉路口至蛋白质组轴。通过调节这些转录后事件，RBP与通过与不同的形态学和/或营养外细胞外信号连接来控制蛋白质表达水平和神经发生。绑定的mRNA可以包含不同的转录mRNA子集并形成我们所谓的“ RNA-Operons”。这些RNA - operon还响应外部提示，可立即转化为蛋白质，从而在关键的细胞事件中快速调整蛋白质水平。然后，这些RNA - operon对环境信号响应，从而使给定的mRNA迅速翻译成特定细胞事件所需的蛋白质。我们确定了一个新皮层RNA-Operon，该新皮层由RBP组成，该RBP结合了六个新皮质mRNA，其特征在于，其特征在其翻译前五天至少五天。据我们所知，这是RBP在任何系统中结合六个叉子mRNA的子集的第一个证据，包括开发新皮层。此外，我们确定了丘脑形态信号，该信号影响了这种新皮质RBP的磷酸化状态，并增加了新皮质叉的转录因子的蛋白质水平。这串联的事件发生在新皮层神经元完成其神经突发育之前。实际上，新皮层RBP和丘脑形态学都会影响新皮质神经发生。因此，我们的中心假设是，这种新皮质RNA - operons的丘脑形态学调节的机制对于新皮质神经元的亚型的时空规范至关重要。因此，我们将确定（1）新皮质RNA操纵子在新皮层投射神经元及其树突分化中的机制；（2）丘脑形态学对新皮质RNA-Operon依赖性规范的作用。为此，我们将使用神经解剖学，细胞，分子和遗传方法的优雅组合。该提案的发现将提供先前未识别的在新皮层神经元亚型的总规范的转录后控制的分子机制，这可能为治疗不同神经发育障碍的新途径开放。