Precisely controlling endogenous protein dosage in hPSCs and derivatives to model FOXG1 syndrome

Wenliang Zhu, Boya Zhang, Mengqi Li, Fan Mo, Tingwei Mi, Yihui Wu, Zhaoqian Teng, Qi Zhou (), Wei Li () and Baoyang Hu ()
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Wenliang Zhu: Chinese Academy of Sciences
Boya Zhang: Chinese Academy of Sciences
Mengqi Li: Chinese Academy of Sciences
Fan Mo: Chinese Academy of Sciences
Tingwei Mi: Chinese Academy of Sciences
Yihui Wu: Chinese Academy of Sciences
Zhaoqian Teng: Chinese Academy of Sciences
Qi Zhou: Chinese Academy of Sciences
Wei Li: Chinese Academy of Sciences
Baoyang Hu: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract Dosage of key regulators impinge on developmental disorders such as FOXG1 syndrome. Since neither knock-out nor knock-down strategy assures flexible and precise protein abundance control, to study hypomorphic or haploinsufficiency expression remains challenging. We develop a system in human pluripotent stem cells (hPSCs) using CRISPR/Cas9 and SMASh technology, with which we can target endogenous proteins for precise dosage control in hPSCs and at multiple stages of neural differentiation. We also reveal FOXG1 dose-dependently affect the cellular constitution of human brain, with 60% mildly affect GABAergic interneuron development while 30% thresholds the production of MGE derived neurons. Abnormal interneuron differentiation accounts for various neurological defects such as epilepsy or seizures, which stimulates future innovative cures of FOXG1 syndrome. By means of its robustness and easiness, dosage-control of proteins in hPSCs and their derivatives will update the understanding and treatment of additional diseases caused by abnormal protein dosage.

Date: 2019
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DOI: 10.1038/s41467-019-08841-7

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