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/摘要人脑皮质包含分布在数十个的细胞类型的惊人多样性功能区域，在早期发育期间出现了明显统一的神经上皮。它有很长的时间假设脑发育异常和基因涉及的基因突变与神经发育的精神疾病会以多种方式影响大脑的发育，但我们目前缺乏可扩展的工具来询问其对专门细胞类型开发的影响。星形胶质细胞代表了一种高度多样化的细胞类别，该类别大致分为几种基本类型。星形胶质细胞在晚期发展中出现，星形胶质细胞亚型的选择性脆弱性是突变或环境扰动可能是精神疾病或寨卡病毒感染中不同表型的基础。但是，发展起源，分子特征和亚型规范的机制较差理解。目前，我们缺乏研究人类星形胶质细胞亚型及其发育的实验方法。我们的初步数据表明，在妊娠中期，径向神经胶质亚型可能会偏向生成人类星形胶质细胞的不同亚型。在拟议的项目中，我们建议通过映射扩展这一发现从多个发育的多个阶段，细胞分化的时间动力学分化了。我们还将确定是否在雪貂中发生类似的发展动态，这可以用作代替人体组织并实现体内功能研究。其次，我们将确定皮质径向胶质细胞亚型和星形胶质细胞亚型。我们的初步研究预测，星形胶质细胞的形态上不同的亚型解剖学上不同的生发壁细分市场，我们建议将这些形态直接注册到转录组使用单细胞mRNA测序的身份。最后，我们的目标是了解不同的径向神经胶质亚型是否贡献了不同的细胞类型大脑皮层。为了解决这个问题，我们建议将异种移植实验执行脑。我们将将这种方法与单细胞测序结合在一起，并在计算机分析中共同包含我们的数据拥有成人人皮层的现有资源，以揭示哪些分子亚型可能从皮质祖细胞的转录 - 不同亚型。