PT  - JOURNAL ARTICLE
AU  - Ranjie Xu
AU  - Andrew T Brawner
AU  - Shenglan Li
AU  - JingJing Liu
AU  - Hyosung Kim
AU  - Haipeng Xue
AU  - Zhiping P. Pang
AU  - Woo-Yang Kim
AU  - Ronald P. Hart
AU  - Ying Liu
AU  - Peng Jiang
TI  - Reversing Abnormal Neural Development by Inhibiting OLIG2 in Down Syndrome Human iPSC Brain Organoids and Neuronal Mouse Chimeras
AID  - 10.1101/462739
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 462739
4099  - http://biorxiv.org/content/early/2019/03/23/462739.short
4100  - http://biorxiv.org/content/early/2019/03/23/462739.full
AB  - Neurodevelopmental disorder Down syndrome (DS) is the most common genetic origin of intellectual disability. Little has been achieved to reverse the abnormal brain development in DS. Using human induced pluripotent stem cells (hiPSCs), we demonstrate that the population of OLIG2-expressing ventral forebrain neural progenitors is overabundant in the cells derived from DS hiPSCs, which results in excessive production of subclass-specific GABAergic interneurons in DS cerebral organoids and causes impaired recognition memory in DS human neuronal chimeric mice. Overexpression of OLIG2 in DS directly upregulates the expression of interneuron lineage-determining transcription factors. Importantly, knockdown of OLIG2 largely reverses the abnormal global gene expression profile of early stage DS neural progenitors, reduces interneuron population in DS organoids and chimeric mouse brains, and improves behavioral performance of DS chimeric mice. Therefore, OLIG2 is a potential target for developing personalized prenatal therapeutics for intellectual disability in subjects with DS.