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

Impact of LZTR1 Mutations on Oligodendrocyte Development and Function

LZTR1 突变对少突胶质细胞发育和功能的影响

基本信息

批准号：
10348322
负责人：
RONALD R WACLAW
金额：
$ 43.73万
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：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348322
关键词：
Adaptor Signaling Protein Address Alleles Animals BRAF gene Biology Brain Cardiovascular system Data Defect Development Disease Embryo Exhibits Family member Functional disorder Gene Dosage Gene Expression Gene Expression Profile Gene Mutation Genes Genetic Models Goals Growth Heart Abnormalities Human KRAS2 gene LacZ Genes Learning Disabilities Link Live Birth MAP Kinase Gene Malignant Neoplasms Mental Retardation Modeling Mus Mutate Mutation NF1 gene Neuraxis Neurocognitive Neuronal Dysfunction Neurons Noonan Syndrome Oligodendroglia PTPN11 gene Pathway interactions Patients Phenotype Play Proteins RAF1 gene Regulation Reporter Reporting Research Role Series Signal Transduction Syndrome System Telencephalon Testing Ubiquitination autosomal dominant mutation base cell type cellular development conditional mutant craniofacial experimental study gain of function gene function human disease improved loss of function loss of function mutation mouse model mutant myelination oligodendrocyte lineage oligodendrocyte progenitor postnatal prevent progenitor ras Proteins single-cell RNA sequencing stem cells transcriptome white matter

项目摘要

Abstract The BTB Kelch family member gene LZTR1 is an upstream regulator of RAS/MAPK signaling and is mutated in both cancers and RASopathy syndromes. Lztr1 is an unusual RASopathy gene that is observed in both autosomal dominant and recessive examples of Noonan Syndrome. Mouse models to study the cellular impact of Lztr1 deficiency have been challenging due to the lethality of germline mutants and cardiac defects. Therefore, the role of Lztr1 in the central nervous system remains largely unknown. Our preliminary data from a newly generated telencephalon specific Lztr1 conditional mutant revealed enriched activation of the MAPK pathway in the white matter region containing the myelinating oligodendrocytes (OLs). In addition, Lztr1 conditional mutants show defects in the expression of stage specific markers of OL development. Single cell RNA sequencing reveal that Lztr1 is expressed in both progenitor and mature stages of OL development. Here we propose to develop new mouse models to address the role of Lztr1 in OL biology. In the first aim, we will test the requirement of Lztr1 during OL development by generating cell type specific conditional mutants at early and late stages of OL development. We will also generate a mouse model for the dominant Lztr1 mutation Y193H and develop an allelic series to test how Lztr1 gene dosage impacts OLs development. In the second aim, we will test if mis- expression of Lztr1 impacts the OL lineage by lowering RAS/MAPK signaling. We will also test if expression of Lztr1 improves aberrant RAS/MAPK activation and OL phenotypes in Nf1 RASopathy mouse models. Finally, we will identify a core RASopathy gene expression signature in the OL lineage by comparing transcriptomes of Lztr1 and Nf1 mouse models. These studies will identify the specific roles of Lztr1 during distinct stages OL development and provide new mouse models key to understanding Lztr1 signaling mechanism and RASopathy biology.

摘要