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Developmental Timing During Cortical Development

皮质发育期间的发育时间

基本信息

批准号：
10613569
负责人：
Tomasz Nowakowski
金额：
$ 39.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613569
关键词：
Address Adult Anatomy Area Astrocytes Bar Codes Biological Models Brain CRISPR/Cas technology Categories Cell Differentiation process Cell Lineage Cells Cerebral cortex Characteristics Classification Comparative Study Competence DNA Sequence Alteration Data Development Event Experimental Models Ferrets Fiber Gene Expression Generations Genes Genetic Goals Grant Heterogeneity Human Individual Knowledge Maps Mental disorders Methods Modeling Molecular Morphology Mus Mutation Neurodevelopmental Disorder Neuroglia Neurons Newborn Infant Oligodendroglia Pathway interactions Pattern Phenotype Pregnancy Primates Production Protoplasmic Astrocyte Radial Resources Rodent Second Pregnancy Trimester Series Slice Specific qualifier value Swelling TCF7L2 gene Technology Testing Time Transplantation Ventricular Viral Work Xenograft procedure ZIKV infection brain tissue cell cortex cell fate specification cell type developmental neurobiology experimental study human tissue in silico in vivo innovation innovative technologies knock-down molecular marker molecular subtypes neonatal brain neonatal mice nerve stem cell neuroepithelium postmitotic progenitor segregation single cell mRNA sequencing single cell sequencing stem cells subventricular zone tool transcription factor transcriptomics

项目摘要

Summary/Abstract The human cerebral cortex contains an astonishing diversity of cell types distributed across dozens of functional areas, which emerge during early development for an apparently uniform neuroepithelium. It has long been hypothesized that genetic mutations underlying brain development abnormalities and genes implicated in neurodevelopmental psychiatric disorders can impact brain development in a variety of ways, but we currently lack scalable tools for interrogating their impact on the development of specialized cell types. Astrocytes represent a highly diverse cell class that is broadly categorized into a handful of cardinal types. Astrocytes emerge in late development, and selective vulnerabilities of astrocyte subtypes to mutations or environmental perturbations may underlie distinct phenotypes in psychiatric disorders or in Zika virus infection. However, developmental origins, molecular characteristics, and mechanisms of subtype specification are poorly understood. We currently lack experimental methods to study human astrocyte subtypes and their development. Our preliminary data suggest that at mid-gestation, radial glia subtypes may be biased towards generating different subtypes of human astrocytes. In the proposed project we propose to extend this finding by mapping the temporal dynamics of cellular differentiation from radial glia subtypes across multiple stages of development. We will also determine whether similar developmental dynamics take place in ferret, which could serve as a substitute to human tissue and enable in vivo functional studies. Secondly, we will determine developmental lineage relationships between cortical radial glia subtypes and astrocyte subtypes. Our preliminary studies predict morphologically distinct subtypes of astrocytes emerge from anatomically distinct germinal niches, and we propose to directly register these morphotypes to transcriptomic identities using single cell mRNA sequencing. Finally, our goal is to understand whether distinct radial glia subtypes contribute distinct cell types of the cerebral cortex. To address this question, we propose to perform xenotransplantation experiments into mouse brain. We will combine this approach with single cell sequencing, and in silico analyses co-embedding our data with existing resources from adult human cortex to reveal what molecular subtypes may emerge from transcriptomically- distinct subtypes of cortical progenitor cells.

摘要/文摘