权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A Conserved RNA Binding Protein Regulates RNAs Critical for Neurodevelopment

一种保守的 RNA 结合蛋白调节对神经发育至关重要的 RNA

基本信息

批准号：
10617285
负责人：
Carly L Lancaster
金额：
$ 4.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617285
关键词：
Adaptive Behaviors Adult Affect Alternative Splicing Axon Binding Biochemical Brain Cells Clinical Complex Defect Deposition Development Diagnosis Disease Drosophila genus Drosophila melanogaster Etiology Event Functional disorder Gene Expression Regulation Genes Genetic Genetic Techniques Guanine Nucleotide Exchange Factors Heritability Hippocampus Human Hypermethylation Impairment Individual Inherited Intellectual functioning disability Introns Lesion Link Locomotion Mediating Memory Mentors Messenger RNA Methyltransferase Modeling Modification Molecular Morphology Mushroom Bodies Mutate Mutation Nature Nervous System Neurodevelopmental Disorder Neurologic Neuronal Differentiation Neurons Nuclear Orthologous Gene Pathogenesis Pathway interactions Patients Play Polyadenylation Population Post-Transcriptional Regulation Protein Isoforms Proteins RNA RNA Splicing RNA, Messenger, Splicing RNA-Binding Proteins Regulation Research Project Grants Role Synaptic plasticity System TRIO gene Testing Tissues Training Transcript Vertebrates Work Zinc Fingers analog axon guidance brain dysfunction brain morphology career development clinical heterogeneity disease heterogeneity epitranscriptomics experience inhibitor insight life time cost loss of function mutation model organism neurodevelopment neuron development novel posttranscriptional protein expression protein function rho spatiotemporal transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY Intellectual disability is a common neurodevelopmental disorder characterized by limited intellectual functioning and impaired adaptive behavior. The clinical heterogeneity of intellectual disability is reflected by extreme genetic complexity, leaving etiology unresolved in over 60% of diagnosed patients. Underscoring this complexity, lesions in more than 700 genes have been linked to intellectual disability. Critically, emerging evidence suggests that this diverse group of these genes converge on a limited set of molecular pathways, principally those critical for brain development and function. This convergence suggests that studies of monogenic, experimentally tractable forms of intellectual disability can provide molecular insight into mechanisms common to all forms of the disease. Interestingly, many of the genes linked to intellectual disability encode RNA binding proteins (RBPs) that play critical roles in post-transcriptional regulation of gene expression. My mentors’ labs co-discovered one such monogenic form of intellectual disability caused by loss of function mutations in the ubiquitously expressed RBP ZC3H14. To discover why mutations in the ZC3H14 gene impair brain function, we have developed an experimentally tractable model of ZC3H14 loss by deleting the ortholog, Nab2, in the fruit fly Drosophila melanogaster. This work has revealed that Nab2 is expressed in all cells but required specifically in neurons within the developing nervous system to support axon guidance, locomotion, and olfactory memory. However, the identity of ZC3H14/Nab2-regulated RNAs as well as mechanisms that elevate ZC3H14/Nab2 function in neurons remain elusive. Recently, my labs have uncovered evidence for a novel role of Nab2 as a regulator of alternative splicing through inhibition of N6-methyladenosine (m6A) deposition on a subset of neuronally enriched mRNAs, representing a critical layer of epitranscriptomic regulation of gene expression during neuronal development. Thus, I will test the hypothesis that Nab2 governs m6A-dependent expression of key neuronal targets by binding their pre-mRNA transcripts and inhibiting m6A hypermethylation to govern proper brain morphology and function here by focusing on one Nab2-regulated transcript, trio, which displays aberrant intron retention upon loss of Nab2. The Trio protein is conserved in vertebrates, the TRIO gene is mutated in a dominant form of human intellectual disability, and Trio plays a key role in axon guidance and neuronal morphology. The Specific Aims of this project are to: 1) define the role of Nab2 as a regulator of m6A-dependent expression of neuronally-enriched transcripts; and 2) examine how Nab2-dependent regulation of Trio expression governs development of axon tracts in the Drosophila mushroom body, an analog of the hippocampus that supports olfactory and gustatory memory. Successful completion of the proposed Aims will provide insights into an apparently conserved pathway linking Nab2 to Trio expression through a neuron-specific role in m6A-regulated splicing, uncovering more general links between m6A, splicing, and neurodevelopmental defects in humans. The proposed collaborative research project will provide me with an optimal training experience.

项目摘要智力残疾是一种常见的神经发育障碍，其特征是智力功能受限和受损的适应行为。智力残疾的临床异质性反映在极端的遗传复杂性，超过60%的确诊患者的病因尚未解决。强调这种复杂性，病变超过700个基因与智力残疾有关。重要的是，新出现的证据表明，这些不同的基因集中在一组有限的分子途径上，主要是那些对大脑的发育和功能。这种趋同性表明，单基因的研究，实验上容易处理，智力残疾的形式可以提供对所有形式疾病共同机制的分子见解。有趣的是，许多与智力残疾有关的基因编码RNA结合蛋白（RBP），在基因表达的转录后调节中起关键作用。我导师的实验室共同发现了一个由广泛表达的RBP中的功能缺失突变引起的单基因形式的智力残疾 ZC3H14为了发现ZC 3 H14基因突变损害脑功能的原因，我们开发了一种果蝇中删除直系同源基因Nab 2导致ZC 3 H14丢失的实验易处理模型黑腹菌这项工作揭示了Nab 2在所有细胞中表达，但在神经元中特异性需要在发育中的神经系统中支持轴突引导、运动和嗅觉记忆。然而，在这方面， ZC 3 H14/Nab 2调节的RNA的身份以及提高ZC 3 H14/Nab 2功能的机制，神经元仍然难以捉摸。最近，我的实验室发现了证据，证明Nab 2作为一种调节剂，选择性剪接通过抑制N6-甲基腺苷（m6 A）沉积在一个子集的神经富集 mRNA，代表了神经元生长过程中基因表达的表转录调控的关键层，发展因此，我将检验Nab 2控制关键神经元m6 A依赖性表达的假设。通过结合它们的前mRNA转录物和抑制m6 A超甲基化来控制适当的大脑形态学和功能，这里集中在一个Nab 2调节的转录本，三，它显示异常内含子失去Nab 2后的保留。Trio蛋白在脊椎动物中是保守的，TRIO基因以显性突变， Trio是人类智力残疾的一种形式，Trio在轴突引导和神经元形态学中起着关键作用。的本项目的具体目的是：1）确定Nab 2作为m6 A依赖性表达的调节剂的作用，神经元富集的转录本;和2）检查Nab 2依赖性调节Trio表达如何控制果蝇蘑菇体中轴突束的发育，海马体的类似物，嗅觉和味觉记忆。成功完成拟议的目标将提供深入了解通过在m6 A调节的神经元特异性作用将Nab 2与Trio表达连接的明显保守的途径剪接，揭示了m6 A，剪接和人类神经发育缺陷之间的更普遍的联系。的建议的合作研究项目将为我提供最佳的培训经验。