Roles for uniquely human enhancers in brain development and WNT signaling

人类独特的增强子在大脑发育和 WNT 信号传导中的作用

基本信息

批准号：
10577092
负责人：
Debra Silver
金额：
$ 62.41万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-09 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577092
关键词：
Acceleration Address Agonist Apical Behavior Biological Assay Biological Process Brain Cell Communication Cell Cycle Cells Cerebral cortex Code Cognition Complex Data Set Development Embryo Enhancers Evolution Exhibits Gene Expression Generations Genes Genetic Genome Genomic approach Genomics Goals Human Image Immunofluorescence Immunologic In Vitro Individual Intellectual functioning disability Luciferases Macaca Modeling Modification Molecular Mus Mutation Neocortex Neuroanatomy Neuroglia Neurons Nucleotides Organoids Pan Genus Phenotype Positioning Attribute Primates Proliferating Regulation Regulator Genes Regulatory Element Reporter Research Role Schizophrenia Signaling Molecule Structure Testing Untranslated RNA Variant WNT Signaling Pathway autism spectrum disorder brain size cell cortex cell immortalization cognitive capacity epigenome editing experimental study fascinate imaging approach induced pluripotent stem cell innovation insight mouse model neocortical nerve stem cell nervous system disorder neurogenesis neuropsychiatric disorder neuroregulation nonhuman primate progenitor receptor self-renewal single-cell RNA sequencing tool

项目摘要

ABSTRACT Humans diverge from other primates in numerous ways including their neuroanatomy and cognitive capacities. Human-specific features are particularly prominent in the cerebral cortex, which has undergone an expansion in size and acquired unique cellular composition and circuitry. Many of these features arose through modifications to cortical development, explained by human-specific gene expression. However, how human-specific gene expression explains divergent brain development is poorly understood. This proposal aims to fill that gap by investigating how non-coding regulatory loci impact human-specific brain development. Specifically, we focus on human accelerated regions (HARs), which are ultra-conserved sequences which have rapidly acquired mutations in the human lineage. HARs frequently physically associate with neurodevelopmental genes, and at least 50% of HARs have enhancer activity in human neural cells. Further, HARs are broadly associated with neurological disorders. Yet, biological functions for HARs in brain development remain largely unknown. Our group discovered HARE5, which shows divergent human-chimpanzee (Hs-Pt) enhancer activity in the developing mouse brain, due to just 4 mutations over 600 conserved nucleotides. HARE5 activates expression of Fzd8, a receptor in the WNT signaling pathway which is implicated in brain size and neurological disease. We have generated humanized HARE5 mouse models which exhibit expanded progenitor and neuron number and enlarged brains. We have additionally discovered new HARs, which like HARE5, are predicted to impact WNT signaling. This proposal will test the central hypothesis that evolutionary modifications of HAR enhancer activity modulate WNT signaling to control neural progenitor dynamics in the developing brain. Our proposal leverages our expertise and unique genetic tools, including mouse models, and human and non-human primate iPSCs and organoids. We will investigate mechanisms of HARE5 function in mouse models (Aim 1) and in cortical organoids generated from human and non-human primate iPSCs (Aim 2). We will then test roles for 12 WNT-associated HARs in neurogenesis (aim 3). Upon completion of this study, we will gain valuable insights into the developmental underpinnings of human cognitive capacities which can inform the basis for neuropsychiatric diseases.

抽象的人类在许多方面与其他灵长类动物不同，包括神经解剖学和认知能力。人类特有的特征在大脑皮层中尤为突出，大脑皮层经历了扩张大小并获得独特的细胞组成和电路。其中许多功能是通过修改而产生的皮质发育，用人类特异性基因表达来解释。然而，人类特有的基因如何人们对于大脑发育发散性的表达解释知之甚少。该提案旨在通过以下方式填补这一空白研究非编码调控基因座如何影响人类特定的大脑发育。具体来说，我们专注于人类加速区（HAR），这是一种高度保守的序列，已迅速获得人类谱系中的突变。 HAR 通常与神经发育基因有物理联系，并且在至少 50% 的 HAR 在人类神经细胞中具有增强子活性。此外，Hars与神经系统疾病。然而，HAR 在大脑发育中的生物学功能仍然很大程度上未知。我们的小组发现了 HARE5，它在发育中的小鼠大脑，由于 600 多个保守核苷酸中仅有 4 个突变。 Hare5激活表达 Fzd8 是 WNT 信号通路中的一种受体，与大脑大小和神经系统疾病有关。我们已经生成了人源化 HARE5 小鼠模型，该模型表现出祖细胞和神经元数量的增加，并且扩大的大脑。我们还发现了新的 HAR，如 HARE5，预计会影响 WNT 发信号。该提案将检验 HAR 增强子的进化修饰这一中心假设活性调节 WNT 信号传导以控制发育中大脑的神经祖细胞动态。我们的该提案利用了我们的专业知识和独特的遗传工具，包括小鼠模型、人类和非人类模型灵长类 iPSC 和类器官。我们将研究小鼠模型中 HARE5 功能的机制（目标 1）和在人类和非人类灵长类 iPSC 产生的皮质类器官中（目标 2）。然后我们将测试角色 12 WNT 相关的 HAR 在神经发生中的作用（目标 3）。完成本研究后，我们将获得宝贵的见解进入人类认知能力的发展基础，这可以为神经精神疾病。