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1.
Nat Commun ; 14(1): 3962, 2023 07 05.
Article in English | MEDLINE | ID: mdl-37407555

ABSTRACT

Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases.


Subject(s)
Huntington Disease , Neurodegenerative Diseases , Mice , Animals , Humans , Disease Models, Animal , Zebrafish/genetics , Zebrafish/metabolism , Huntington Disease/metabolism , Neurons/metabolism , Neurodegenerative Diseases/metabolism , Huntingtin Protein/genetics , Huntingtin Protein/metabolism
2.
Stem Cell Reports ; 8(2): 318-333, 2017 02 14.
Article in English | MEDLINE | ID: mdl-28089671

ABSTRACT

In early mouse pre-implantation development, primitive endoderm (PrE) precursors are platelet-derived growth factor receptor alpha (PDGFRα) positive. Here, we demonstrated that cultured mouse embryonic stem cells (mESCs) express PDGFRα heterogeneously, fluctuating between a PDGFRα+ (PrE-primed) and a platelet endothelial cell adhesion molecule 1 (PECAM1)-positive state (epiblast-primed). The two surface markers can be co-detected on a third subpopulation, expressing epiblast and PrE determinants (double-positive). In vitro, these subpopulations differ in their self-renewal and differentiation capability, transcriptional and epigenetic states. In vivo, double-positive cells contributed to epiblast and PrE, while PrE-primed cells exclusively contributed to PrE derivatives. The transcriptome of PDGFRα+ subpopulations differs from previously described subpopulations and shows similarities with early/mid blastocyst cells. The heterogeneity did not depend on PDGFRα but on leukemia inhibitory factor and fibroblast growth factor signaling and DNA methylation. Thus, PDGFRα+ cells represent the in vitro counterpart of in vivo PrE precursors, and their selection from cultured mESCs yields pure PrE precursors.


Subject(s)
Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Endoderm/cytology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Angiopoietin-1 , Animals , Biomarkers , Blastocyst/cytology , Blastocyst/metabolism , Cell Differentiation/genetics , Cell Line , Cells, Cultured , DNA Methylation , Embryonic Development/genetics , Endoderm/metabolism , Epigenesis, Genetic , Gene Expression Regulation, Developmental , Mice , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction
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