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The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

RNA 结合蛋白 FMRP 促进髓鞘生长

基本信息

批准号：
10039005
负责人：
Caleb Andrew Doll
金额：
$ 42.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039005
关键词：
Automobile Driving Axon Binding Proteins Bioinformatics Brain Cell Lineage Cell Nucleus Cells Cognition Defect Development Disease Distal Essential Genes Event FMR1 Foundations Fragile X Syndrome Future Gene Expression Genes Genetic Translation Growth Heritability Individual Intellectual functioning disability Investigation Learning Length Location Membrane Memory Messenger RNA Molecular Monitor Morphology Myelin Myelin Basic Proteins Myelin Sheath Nervous system structure Neuraxis Neurodevelopmental Disorder Neuroglia Neurons Oligodendroglia Pathogenesis Physiology Play Process Production Protein Biosynthesis RNA-Binding Proteins Regulation Research Role Site Structure Synaptic plasticity Techniques Testing Translating Translational Regulation Translations Visualization Work Zebrafish autism spectrum disorder cell type developmental neurobiology experience flexibility gene function genetic manipulation glial cell development in vivo in vivo evaluation intercellular connection mutant myelination neural circuit oligodendrocyte lineage polarized cell protein expression protein function screening synaptogenesis white matter

项目摘要

Project Summary Cells in the nervous system are highly polarized and intercellular contacts take place at great distance from cell bodies. Oligodendrocytes produce numerous myelin sheaths on independent axons of variable size and physiology, which highlights remarkable flexibility in the production of myelin membrane at the tips of individual distal processes. Moreover, myelination is an activity-dependent process that enhances neuronal function and is required for learning and memory, indicating essential contributions of oligodendrocytes to neural circuit development. Interestingly, myelin deficiencies and altered myelin gene expression have been noted in Fragile X Syndrome, autism spectrum disorders, and a wide array of neurodevelopmental disorders, which indicate essential roles for oligodendrocytes in disease pathogenesis. Our recent evidence indicates that the RNA binding protein fragile x mental retardation protein (FMRP) is required for myelin sheath growth in a mechanism that is dependent on the translational regulation of mRNA. However, the genes coordinating initial myelin sheath growth are unknown, as are the subcellular mechanisms of mRNA regulation in oligodendrocytes. We hypothesize that FMRP regulates the localization and translation of mRNAs required for myelin sheath growth in oligodendrocytes. We will test this hypothesis using zebrafish, building upon our expertise in cell-type specific visualization and manipulation of gene expression in the developing nervous system. Our experimental plan has two parts. First, we will identify the precise location of FMRP binding on target mRNAs. Second, we will visualize the subcellular localization of mRNAs predicted to underlie myelin sheath growth and manipulate target gene expression specifically in oligodendrocytes of living zebrafish. This project has the potential to uncover the essential genes required for initial myelin sheath growth and will lay the foundation for future investigations into the mechanism of subcellular activity-dependent regulation of mRNA translation during myelination.

项目总结