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

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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.