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Genetic approaches to address oligodendrocyte progenitor cell diversity

解决少突胶质细胞祖细胞多样性的遗传方法

基本信息

批准号：
10580824
负责人：
RONALD R WACLAW
金额：
$ 19.88万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580824
关键词：
Address Age Alleles Animal Model Antibodies Automobile Driving Axon Behavioral Brain Cell Count Cells Cellular biology Compensation Complex Data Defect Development Differentiation Antigens Doxycycline DsRed Exhibits FURIN gene Future Gene Expression Gene Expression Profiling Generations Genes Genetic Genetic Variation Goals Heterogeneity Homeobox Homeobox Genes MAP Kinase Gene Modeling Mouse Protein Mus Mutation Myelin NF1 gene Oligodendroglia Pathway interactions Phenotype Population Process Production Proteins Regulation Reporter Research Role Signal Pathway Signal Transduction Stem Cell Development Testing Time Transgenes cell cortex conditional mutant gain of function gene function genetic approach genetic manipulation in vivo loss of function mouse model mutant myelination neurogenesis novel novel marker oligodendrocyte lineage oligodendrocyte progenitor postnatal prevent progenitor single-cell RNA sequencing stem cells tool transcription factor transcriptome sequencing white matter

项目摘要

Abstract Oligodendrogenesis is a complex process that requires changes in transcription factor expression for the generation, expansion, and differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs) that produce myelin. The overall goal of this proposal is to focus on understanding the diversity of the OPC stage in the process. Our gene expression screen to identity novel OPC markers revealed the homeobox gene Gsx1 exhibits temporal expression in OPCs during development. Here we propose to develop new mouse models to address the role of Gsx1 in OPC biology. In the first aim, we will test if Gsx1 is a stage specific regulator in OPCs and generate an OPC specific conditional mutant to determine if altering Gsx1 gene function causes changes in OPC expansion, OL differentiation, and/or myelination. We will also test if the closely related gene, Gsx2, compensates for the loss of Gsx1 in OPCs. In the second aim, we will test if sustained Gsx1 expression throughout OL development promotes OPC generation and subsequently OL differentiation and myelination using a temporally controlled doxycycline regulated gain-of-function model. In the third aim, we will utilize the Gsx1 lineage to reveal OPC diversity during postnatal oligodendrogenesis by generating a novel Gsx1 reporter allele using Timer Fluorescent Protein. These studies will identify the specific roles of Gsx1 during the OPC stage of OL development and provide new mouse models key for understanding the complex regulation of OPCs during oligodendrogenesis.

摘要