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Novel Functions of OLIG2 in Regulating Human Interneuron Production in Health and Disease

OLIG2 在健康和疾病中调节人类中间神经元产生的新功能

基本信息

批准号：
9906920
负责人：
Peng Jiang
金额：
$ 31.54万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906920
关键词：
Animal Model Brain CRISPR/Cas technology Cell Transplantation Cells Chromosome 21 Cognitive deficits Collaborations Comb animal structure Development Disease Down Syndrome Electrophysiology (science)Embryo Embryonic Development Equilibrium Family Ganglia Gene Dosage Generations Genes Health Human Human Chromosomes Intellectual functioning disability Interneurons Knock-out Light Link Maps Molecular Biology Mus Mutation Neurons Patients Pattern Population Production Property Prosencephalon Rodent Role Structure Synaptic plasticity Syndrome System Technology Telencephalon Testing Therapeutic Transplantation Trisomy brain tissue causal variant genome editing in vivo induced pluripotent stem cell insight mouse model nerve stem cell nervous system disorder neural circuit novel overexpression progenitor relating to nervous system transcription factor

项目摘要

Disruption of excitatory/inhibitory balance (E/I imbalance) is one of the underlying causes of cognitive deficit of Down syndrome (DS), a neurodevelopmental disease characterized by triplication of human chromosome 21 (HSA21). This E/I imbalance in DS is largely resulted from overproduction of GABAergic interneurons. To study the mechanisms of intellectual disability of DS, we must better understand how interneuron production from neural progenitor cells (NPCs) is regulated during development. OLIG genes, including OLIG1 and OLIG2, are mapped to HSA21 and triplicated in DS. Studies in mouse models demonstrate that during embryonic development, both Olig1 and 2 are abundantly expressed in the ganglionic eminence, a brain structure located in the ventral embryonic telencephalon and from where most cortical interneurons are born. Moreover, Olig genes critically regulate interneuron production. Notably, expression of OLIG genes is starkly different in the human versus rodent developing ganglionic eminence. We found that differentiation of human induced pluripotent stem cell (hiPSCs) to ventral forebrain NPCs recapitulated the previous findings in human brain tissue that OLIG2 was expressed in a subpopulation of human NPCs in the ganglionic eminence. In contrast, OLIG1 was expressed in very few of these NPCs and had a complimentary expression pattern with OLIG2. Up to now, the functions of human OLIG genes in the development of human GABAergic neuron is largely unknown. Using DS patient-derived hiPSCs, we further identified that OLIG2 was overexpressed in the DS hiPSC-derived ventral forebrain NPCs. Therefore, we hypothesize that abnormal expression of OLIG genes, particularly OLIG2, in human DS ventral forebrain NPCs determines the overproduction of GABAergic neurons from these progenitors, which leads to E/I imbalance and significantly contributes to intellectual disability of DS. To test the hypothesis, I proposed three specific aims. Aim 1: to determine the role of OLIG2 in regulating human GABAergic neuron production from normal hiPSCs. We will employ OLIG2 knockout hiPSCs generated by using CRISPR/Cas9 technology to study the role of OLIG2 in human interneuron development. Aim 2: to determine whether OLIG2 is a causal gene of the overproduction of GABAergic neurons in DS. By using control and DS hiPSCs, as well as the DS hiPSCs with normalized OLIG2 gene dosage, we will determine whether overexpression of OLIG2 causes the overproduction of GABAergic neurons in DS. Aim 3: by using a novel humanized neuronal chimeric mouse model, we will further examine interneuron specification of the normal and DS hiPSC-derived ventral forebrain NPCs and their integration and contribution to E/I imbalance in vivo within intact neural circuits. Findings from this proposed study will provide novel insights into the function of OLIG2 in regulating human GABAergic neuron production and shed new light on developing potential therapeutic applications for DS by regulating the expression of OLIG2 gene.

兴奋性/抑制性平衡（E/I失衡）的破坏是认知缺陷的根本原因之一。唐氏综合征（Down syndrome，DS）是一种以人类21号染色体三重化为特征的神经发育性疾病（HSA 21）。这种E/I失衡在很大程度上是由于GABA能中间神经元的过度产生。到要研究DS的智能障碍机制，就必须更好地了解中间神经元的产生神经前体细胞（NPC）的分化在发育过程中受到调节。OLIG基因，包括OLIG 1和OLIG 2，被映射到HSA 21并在DS中三重化。在小鼠模型中的研究表明，在发育过程中，Olig 1和Olig 2都在神经节隆起中大量表达，神经节隆起是一种位于在胚胎端脑的腹侧，也是大多数皮质中间神经元的出生地。此外，奥利基因严格地调节中间神经元的产生。值得注意的是，OLIG基因的表达在不同的组织中截然不同。人类和啮齿动物的神经节隆起我们发现，人类的分化诱导多能干细胞（hiPSC）到腹侧前脑NPC的研究概括了以前在人脑中的发现组织中，OLIG 2在神经节隆起中的人NPC亚群中表达。与此相反， OLIG 1在这些NPC中的极少数中表达，并且与OLIG 2具有互补的表达模式。起来迄今为止，人OLIG基因在人GABA能神经元发育中的功能主要是未知使用DS患者来源的hiPSC，我们进一步鉴定了在DS中OLIG 2过表达。 hiPSC衍生的腹侧前脑NPC。因此，我们假设OLIG基因的异常表达，特别是OLIG 2，在人DS腹侧前脑NPC中决定GABA能神经元的过度产生这导致E/I失衡，并显著促成DS的智力残疾。为了验证这个假设，我提出了三个具体目标。目的1：确定OLIG 2在调节中的作用从正常hiPSC产生人GABA能神经元。我们将采用OLIG 2敲除的hiPSC产生的利用CRISPR/Cas9技术研究OLIG 2在人中间神经元发育中的作用。目标2：确定OLIG 2是否是DS中GABA能神经元过度产生的致病基因。通过使用对照和DS hiPSC，以及具有标准化的OLIG 2基因剂量的DS hiPSC，我们将确定 OLIG 2的过度表达是否导致DS中GABA能神经元的过度产生。目标3：通过使用新的人源化神经元嵌合小鼠模型，我们将进一步研究神经元的中间神经元特化。正常和DS hiPSC衍生的腹侧前脑NPC及其整合和对E/I失衡的贡献在完整的神经回路中。这项拟议研究的结果将为该功能提供新的见解 OLIG 2在调节人GABA能神经元产生中的作用，并为开发潜力提供了新的线索通过调节OLIG 2基因的表达来治疗DS的应用。