Comparative Genomics of Precursor Diversity and Function

前体多样性和功能的比较基因组学

• 批准号: 10375401
• 负责人: Tarik F Haydar
• 金额: $ 66.37万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375401
• 关键词: Age; Apical; Archives; Bioinformatics; Brain; Candidate Disease Gene; Cell Nucleus; Cell division; Cell physiology; Cells; Cerebral cortex; Comparative Study; Complement; Complex; Data; Data Set; Development; Elements; Embryo; Evolution; Factor Analysis; Freezing; Gene Expression; Gene set enrichment analysis; Genes; Genomics; Growth; Human; Imaging Techniques; Immunohistochemistry; In Situ Hybridization; Individual; Label; Lead; Macaca; Macaca mulatta; Mammals; Maps; Molecular; Motor; Mus; Nature; Neocortex; Neuroglia; Neurons; Pan Genus; Pattern; Population; Primates; Process; Property; Radial; Reporting; Resolution; Rodent; Role; Sampling; Sensory; Signal Pathway; Small Nuclear RNA; Specimen; System; Testing; Time; Ventricular; Work; cell behavior; cell type; comparative genomics; deep sequencing; executive function; experimental study; fetal; genomic signature; imaging modality; in vivo; lissencephaly; molecular imaging; neocortical; nerve stem cell; nervous system disorder; neurogenesis; nonhuman primate; novel; prenatal; progenitor; programs; relating to nervous system; sample archive; single-cell RNA sequencing; stem; stem cells; subventricular zone; tissue archive; tool; transcriptome; transcriptome sequencing; transcriptomics

ABSTRACT The neocortex is the most complex cellular system in the natural world, the seat of motor, sensory and executive function. While many of the mechanisms responsible for neocortical formation are known, key aspects of how gene expression and cellular behavior lead to species-specific features of the neocortex remain to be discovered. Recent advances in genomic analysis and in vivo cellular labeling enable study of cortical development at an unprecedented level of resolution. In particular, some human-specific genes and neural precursor cells have been detected and current evidence suggests that increased proliferative capacity and longer neurogenesis times enable the expanded growth of the primate neocortex. In this project using archived tissue, we will comprehensively compare the heterogeneous groups of neural precursor cells in mouse, macaque, chimpanzee and human neocortex. Using single cell and single nucleus RNA sequencing and implementation of novel molecular labeling tools, we will compare genomic signatures and in vivo behavior of these cells to uncover mechanisms of brain growth and evolution. A significant focus of this project will be on a precursor type called the basal radial glial cell (bRGC), thought to have emerged recently in evolution to enable expansion of the primate brain. However, our preliminary experiments uncover multiple groups of bRGCs in mouse neocortex that share key features of bRGCs found in primate brain, contradicting reports suggesting their biased role in primate brain growth. These studies will use emerging evidence and new tools to elucidate species-specific programs controlling neocortical growth.

摘要 新皮层是自然界中最复杂的细胞系统，是运动、感觉和神经活动的所在地。 执行功能虽然许多负责新皮层形成的机制是已知的，关键是 基因表达和细胞行为如何导致新皮层的物种特异性特征仍然存在 等待被发现基因组分析和体内细胞标记的最新进展使皮层神经元的研究成为可能。 以前所未有的分辨率发展。特别是，一些人类特异性基因和神经 已经检测到前体细胞，目前的证据表明，增加的增殖能力和 较长的神经发生时间使灵长类动物新皮层的生长扩大。在这个项目中， 存档的组织，我们将全面比较神经前体细胞的异质群体， 小鼠、猕猴、黑猩猩和人类大脑新皮层。使用单细胞和单核RNA测序 和实施新的分子标记工具，我们将比较基因组签名和体内行为 来揭示大脑生长和进化的机制。该项目的一个重要重点是 一种称为基底放射状胶质细胞（bRGC）的前体类型，被认为是最近在进化中出现的， 使灵长类动物的大脑得以扩展。然而，我们的初步实验发现， 小鼠新皮层中的bRGC与灵长类动物大脑中发现的bRGC具有关键特征，与报告相矛盾 这表明它们在灵长类动物大脑发育中的作用有偏差。这些研究将使用新兴证据和新工具 阐明控制新皮层生长的物种特异性程序。