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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：
10454507
负责人：
RONALD R WACLAW
金额：
$ 23.85万
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454507
关键词：
Address Age Alleles Animal Model Antibodies Automobile Driving Axon Behavioral Brain Cell Count Cells Cellular biology 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 base 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.

摘要少突发育是一个复杂的过程，需要转录因子表达的变化，少突胶质细胞祖细胞（OPCs）的产生、扩增和分化为成熟的产生髓鞘的少突胶质细胞（OL）。本提案的总体目标是重点了解 OPC阶段的多样性。我们的基因表达筛选，以确定新的OPC标志物，揭示了同源框基因Gsx 1在发育过程中在OPCs中表现出时间表达。在此，我们建议开发新的小鼠模型，以解决Gsx 1在OPC生物学中的作用。在第一个目标中，我们将测试Gsx 1是否是一个阶段特异性调节剂，并产生OPC特异性条件突变体，以确定是否改变Gsx 1 基因功能引起OPC扩增、OL分化和/或髓鞘形成的变化。我们还将测试密切相关的基因Gsx 2弥补了OPCs中Gsx 1的缺失。在第二个目标中，我们将测试 Gsx 1在整个OL发育过程中的表达促进OPC生成和随后的OL分化和髓鞘形成，使用时间控制的强力霉素调节的功能获得模型。第三个目标，我们将利用Gsx 1谱系揭示OPC多样性在出生后少突分化，通过产生一种新的 Gsx 1报告等位基因使用计时器荧光蛋白。这些研究将确定Gsx 1在治疗中的具体作用。 OL发育的OPC阶段，并为理解复杂调控提供新的小鼠模型 OPCs在少突发育中的作用。