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PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts II

ABSTRACT: Forced expression of ASCL1, Nurr1, Lmx1a, miRNA-124 and p53shRNA (ANLmp) in fibroblasts reprograms fibroblasts to induced dopaminergic neurons (iDA). While human lung fibroblasts can be converted rapidly and efficiently, iDA of dermal fibroblast is very unefficient and incompleted. To address this issue, we performed time series RNAseq on both lung and dermal fibroblasts during the first several days of ANLmp induced neuron convertion. Bioinformatics analysis revealed the stable fibroblast gene regulatory network (GRN) was a potential repressive factor for iDA in human dermal fibroblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129358 | GEO | 2019/06/17

REPOSITORIES: GEO

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PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts.

Project description:Forced expression of ASCL1, Nurr1, Lmx1a, miRNA-124 and p53shRNA (ANLmp) in fibroblasts reprograms fibroblasts to induced dopaminergic neurons (iDA). While human lung fibroblasts can be converted rapidly and efficiently, iDA of dermal fibroblast is very unefficient and incompleted. To address this issue, we performed time series RNAseq on both lung and dermal fibroblasts during the first four days of ANLmp induced neuron convertion. Bioinformatics analysis revealed the stable fibroblast gene regulatory network (GRN) was a potential repressive factor for iDA in human dermal fibroblasts.

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Cell cycle and P53 gate the direct conversion of human fibroblasts to dopaminergic neurons

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Ascl1, Nurr1 and Lmx1 convert mouse and human fibroblasts into functional dopaminergic neurons without passing through an intermediate precursor state

Project description:Lineage-specific transcription factors, which drive cellular identity during embryogenesis, have been shown to convert cell fate when express ectopically in heterologous cells. Herein, we screened the key molecular factors governing the dopaminergic neuronal specification during brain development for their ability to generate similar neurons directly from mouse and human fibroblasts. Remarkably, we found a minimal set of three factors Mash1, Nurr1 and Lmx1a/b able to elicit such cellular reprogramming. Molecular and transcriptome studies showed reprogrammed DA neurons to faithfully recapitulate gene expression of their brain homolog cells while lacking expression of other catecholaminergic neuronal types. Induced neurons showed spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain DA neurons. The three factors were able to elicit DA neuronal conversion in human fibroblasts from prenatal or adult fibroblasts of healthy donors and a Parkinson’s disease patient. Generation of DA induced neurons from somatic cells might have significant implications in studies of neural development, disease in vitro modeling and cell replacement therapies. We infected mouse embryonic fibroblasts (MEFs) isolated from TH-GFP knock-in mice embryos at E14.5, with lentiviruses expressing the three dopaminergic transcription factors Ascl1, Lmx1a and Nurr1. TH-GFP MEFs infected (Ind) by a pool of the three previously mentioned dopaminergic lentiviruses were shifted in a neuronal medium for 12 days and sorted for GFP-positive cells. Thus we extracted mRNA from Ind-GFP-positive cells and compared them to not infetced (NI) cells by means of RNA-microarray analysis.

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PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts.

Project description:PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts.

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PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts II

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Attenuation of PRRX2 and HEY2 enables efficient conversion of adult human skin fibroblasts to neurons.

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Project description:Recent developments in molecular programming of mesodiencephalic dopaminergic (mdDA) neurons have led to the identification of many transcription factors playing a role in mdDA specification. LIM homeodomain transcription factor Lmx1a is essential for chick mdDA development, and for the efficient differentiation of ES-cells towards a dopaminergic phenotype. In this study, we aimed towards a more detailed understanding of the subtle phenotype in Lmx1a-dr/dr mice. Therefore, microarray analysis was performed, to elucidate the exact molecular programming underlying the neuronal deficits after loss of Lmx1a. Subsequent expression analysis confirmed that Nurr1 is regulated by Lmx1a, and additional downstream targets were identified, like Pou4f1, Pbx1, Pitx2, C130021l20Rik, Calb2 and Rspo2. In line with a specific, rostral-lateral loss of expression of most of these genes during development, Nurr1 and C130021l20Rik were affected in the SNc of the mature mdDA system. Interestingly, this deficit was marked by the complete loss of the Wnt/b-catenin signaling activator Rspo2 in this domain. Expression analysis in Rspo2-/- embryos revealed affected mdDA neurons, partially phenocopying the Lmx1a mutant. Together, in this study we reveal that Lmx1a is essential for a rostral-lateral subset of the mdDA neuronal field, where it might serve a critical function in modulating proliferation and differentiation of mdDA progenitors through the activation of the Wnt activator Rspo2. Microarray expression study comparing 4 samples of homozygous LMX1A dr/dr mice, midbrain E12.5 with a pooled sample of their wt/wt littermates. Two samples were analyzed in opposite dye orientation.

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