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

A Murine Sox10 Dominant Negative COIN Allele for Functional Gene Analysis

用于功能基因分析的鼠 Sox10 显性负 COIN 等位基因

基本信息

批准号：
8484470
负责人：
E Michelle SOUTHARD-SMITH
金额：
$ 7.53万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484470
关键词：
Alleles Animals Autonomic ganglion Breeding Cell Lineage Cells Chimera organism Clinical Code Congenital Disorders Congenital Megacolon Development Developmental Process Disease Dominant-Negative Mutation Embryo Enteral Enteric Nervous System Excision Exhibits Failure Family Functional RNA Ganglia Gastrointestinal Motility Gene Expression Gene Targeting Generations Genes Goals Growth HMG Domain Heterozygote Interruption Intestines Introns Kinetics Knock-in Mouse Maintenance Messenger RNA Mus Muscle Mutant Strains Mice Mutation Nerve Nervous System Physiology Nervous System Trauma Nervous system structure Neural Crest Neuraxis Neuroglia Neurons Normal Statistical Distribution Oligodendroglia Pain Patients Pattern Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Pigmentation physiologic function Play Population Protein Isoforms Proteins Reporter Resistance Role Schwann Cells Sensory Site-Directed Mutagenesis Southern Blotting Spinal Cord Staging Stem cells Temperature Therapeutic Transfection Transgenic Mice Transgenic Organisms Trauma Vertebral column blastocyst cell type gene function gliogenesis homologous recombination in vivo knockout gene member model development motility disorder mouse model mutant novel oligodendrocyte precursor painful neuropathy precursor cell progenitor restoration segregation stem cell population tool transcription factor vector

项目摘要

DESCRIPTION (provided by applicant): Gliogenesis and maintenance of glial cell types are critical to development and function of the nervous system. Sox10 is a developmental transcription factor that is essential for development of multiple glial lineages including oligodendrocytes in the central nervous system as well as neural crest-derived Schwann cells, satellite glia and enteric nervous system neurons and glia in the periphery. Investigating Sox10 function in these distinct populations has been difficult because simple gene knockouts cause complete loss of gene expression in early neural crest progenitors resulting in embryonic lethality. Efforts to temporally induce loss of Sox10 have been hampered by kinetics of mRNA and protein decay. In the context of the R03 mechanism we propose generation of a COnditional INducible ("COIN") dominant negative allele of Sox10 in mice as a novel tool for analysis of gene function. Specific Aim 1 will generate mice bearing a COIN cassette in the Sox10 locus that upon Cre action results in expression of a fluorescently tagged dominant negative Sox10 isoform. Specific Aim 2 will define the effects of the Sox10COIN allele on oligodendrocyte and enteric neural crest-derived lineages before and after COIN inversion. The ability to conditionally disrupt Sox10 expression and function in distinct populations will significantly impact the field by opening avenues for analysis of developmental mechanisms that are relevant for directed differentiation of progenitors cells to treat central and peripheral neuropathies.

描述（由申请人提供）：胶质细胞类型的胶质发生和维持对神经系统的发育和功能至关重要。Sox 10是一种发育转录因子，对多种神经胶质细胞谱系的发育至关重要，包括中枢神经系统中的少突胶质细胞以及神经嵴衍生的许旺细胞、卫星神经胶质细胞和肠神经系统神经元以及外周中的神经胶质细胞。在这些不同的人群中研究Sox10的功能一直很困难，因为简单的基因敲除会导致早期神经嵴祖细胞基因表达的完全丧失，从而导致胚胎死亡。暂时诱导Sox10丢失的努力受到mRNA和蛋白质衰变动力学的阻碍。在R03机制的背景下，我们提出在小鼠中产生Sox 10的C0N诱导（“COIN”）显性负等位基因作为分析基因功能的新工具。特异性目的1将产生在Sox10基因座中携带COIN盒的小鼠，其在Cre作用后导致荧光标记的显性阴性Sox10同种型的表达。具体目标2将定义Sox10COIN等位基因在COIN倒位前后对少突胶质细胞和肠神经嵴衍生谱系的影响。有条件地破坏Sox10在不同群体中的表达和功能的能力将通过为分析与祖细胞定向分化以治疗中枢和外周神经病相关的发育机制开辟途径来显著影响该领域。