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

Nature Communications
Wenliang ZhuBaoyang Hu

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.

References

Jan 1, 1994·Current Topics in Developmental Biology·J D Gold, R A Pedersen
Jan 6, 2004·Science·Carina HanashimaGord Fishell
Jan 3, 2006·Nature Neuroscience·Nicoletta KessarisWilliam D Richardson
Apr 11, 2008·Neuron·Hiromi ShimojoRyoichiro Kageyama
Mar 10, 2009·Genes & Development·Christopher A FasanoSally Temple
Jul 1, 2009·Journal of Medical Genetics·C PhilippeP Jonveaux
Nov 17, 2009·Nature Methods·Kohei NishimuraMasato Kanemaki
Feb 19, 2010·Journal of Medicinal Chemistry·John A McCauleyNigel J Liverton
Aug 26, 2010·European Journal of Human Genetics : EJHG·Nicola Brunetti-PierriPawel Stankiewicz
Jul 9, 2011·Nature Biotechnology·Dirk HockemeyerRudolf Jaenisch
Mar 14, 2012·Nature Reviews. Genetics·Christine Vogel, Edward M Marcotte
Jun 7, 2012·Molecular Syndromology·C FlorianT Bienvenu
Jun 30, 2012·Science·Martin JinekEmmanuelle Charpentier
Sep 25, 2012·Epilepsia·Renzo Guerrini, Elena Parrini
Nov 15, 2012·Proceedings of the National Academy of Sciences of the United States of America·Andrew J HollandDon W Cleveland
Jan 5, 2013·Science·Le CongFeng Zhang
May 17, 2013·Nature·Linfeng WuMichael Snyder
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Jul 19, 2014·Science·Madeline A Lancaster, Juergen A Knoblich
Oct 1, 2014·Epilepsia·Gaetano TerroneStéphane Auvin
Jun 13, 2015·ACS Chemical Biology·Dennis L BuckleyCraig M Crews
Jul 15, 2015·Nature·Andrea RossiDidier Y R Stainier
Jul 28, 2015·Nature Chemical Biology·Hokyung K ChungMichael Z Lin
Jan 30, 2016·Cell·Kevin DalgaardJ Andrew Pospisilik
Mar 15, 2016·Cell Stem Cell·Mohammad A MandegarBruce R Conklin
Oct 13, 2016·Annual Review of Pharmacology and Toxicology·Daniel P Bondeson, Craig M Crews

❮ Previous
Next ❯

Citations

May 10, 2020·Cerebral Cortex·Wendalina TiganiAntonello Mallamaci
Dec 12, 2019·Frontiers in Pediatrics·Nuwan C Hettige, Carl Ernst
Mar 12, 2020·Frontiers in Cellular Neuroscience·Pei-Shan HouCarina Hanashima
Jun 18, 2021·Cell Systems·Nika ShakibaDomitilla Del Vecchio
Sep 26, 2021·Advanced Materials·Sang Ah YiKi-Bum Lee

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
FACS

Software Mentioned

ZEN
LONZA
imageJ
ModFitLT
SMASh
FlowJo

Related Concepts

Related Feeds

CRISPR (general)

Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). CRISPR-Cas system enables the editing of genes to create or correct mutations. Discover the latest research on CRISPR here.

CRISPR for Genome Editing

Genome editing technologies enable the editing of genes to create or correct mutations. Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA sequences in the genome that are recognized and cleaved by CRISPR-associated proteins (Cas). Here is the latest research on the use of CRISPR-Cas system in gene editing.