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Brain development phenotyping of IMPC lethal mutant mice

IMPC致死突变小鼠的大脑发育表型

基本信息

批准号：
10029899
负责人：
NOELLE D DWYER
金额：
$ 58.22万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10029899
关键词：
Address Affect Age Apical Apoptosis Axon Basal lamina Biological Biology Body Size Brain Brain Diseases Candidate Disease Gene Cell Polarity Cell division Cells Cellular Structures Cephalic Child Health Communities Complex Cytokinesis Data Databases Daughter Defect Development Developmental Biology Disease Disease model Dissection Embryo Ethylnitrosourea Etiology Excision Gene Expression Genes Genetic Goals Heterozygote Histologic Histology Histopathology Homozygote Human Human Development Image Intellectual functioning disability International Investigation Kinesin Kinetics Knock-out Knockout Mice Knowledge Labyrinth Lead Libraries Medicine Methods Microtubules Mission Mitosis Modeling Morphogenesis Morphology Mus Mutant Strains Mice Mutate Mutation National Institute of Child Health and Human Development Neural Tube Defects Neuroanatomy Neurodevelopmental Disorder Organ Outcome Phenotype Placenta Process Prosencephalon Proteins Public Health Publishing Research Research Personnel Resources Role Series Shapes Simple Epithelium Spinal Cord Stains Stretching Structural defect Structure Surface Testing Thick Time Tube Ventricular apical membrane base brain abnormalities brain malformation brain size cohort daughter cell developmental disease experience forward genetics gastrulation gene discovery gene function genetic approach improved inner ear development insight mouse genetics mouse model mutant nerve stem cell neural plate neurodevelopment neuromechanism novel organ growth response reverse genetics self-renewal stem cell division tool

项目摘要

Abstract: The mechanisms by which neural stem cells build the brain from a simple epithelial tube is a compelling mystery of biology. Mouse genetics has been one of the most powerful tools to discover the genes and processes involved in building a healthy brain, or in neurodevelopmental disorders that affect brain structure or function. The library of targeted mutations created by the International Mouse Phenotyping Consortium (IMPC) provides a highly valuable resource for understanding those genes and processes. Many mutations that cause neurodevelopmental phenotypes are lethal, either due to the brain defect or to pleiotropic functions of the gene in other organs essential for viability. Thus, the bank of lethal mutants at IMPC provides an enriched set of candidate genes required for brain development. However, changes in brain structure or wiring are difficult to detect without the right tools and expertise. We propose to apply our expertise to phenotype selected knockout lines that are likely to have neurodevelopment defects, based on gene expression, function, and/or known mutation in a human developmental disorder. This is in response to an FOA to characterize developmental defects in lethal IMPC mutants. We will combine non-hypothesis driven gross phenotyping with hypothesis-driven analysis of a few selected brain development mutants. To add value and efficiency to this screen, subsets of mutants will also be tested by co-investigators for inner ear development phenotypes, and placenta, gastrulation, or neural tube defects. For the first tier of phenotyping, lines will be tested for age of lethality and phenotyped for gross abnormalities of brain, inner ear, spinal cord, and body development. Tier 2 phenotyping will incorporate histopathology of brain, inner ear, and placenta, since many structural defects in these organs cannot be ascertained without sectioning and staining. We will test for proliferation, layering, and axon tract defects. Tier 3 phenotyping will focus on a small number of mutants with both abnormal brain phenotypes and gene functions in cytokinesis, to address our hypothesis: that different defects in cytokinesis of cortical neural stem cells underlie a variety of brain malformations. We will make use of methods we have established for quantitative analysis of cytokinetic furrowing and abscission defects in developing mouse cortex. In all stages of phenotyping, heterozygotes and homozygotes will be compared to controls quantitatively and with statistical rigor. Data will be shared with IMPC for the benefit of the community. Our team of three investigators has a combined >50 years of expertise working on cellular bases of organ development in the mouse model, and forward and reverse genetics. Through this project , we will discover new mouse models for developmental disorders of the brain, inner ear, and placenta, and will provide important new insights into the mechanisms of neural stem cell divisions and cellular defects underlying brain malformations.

摘要：神经干细胞从简单上皮管构建大脑的机制尚不清楚