1. Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia.
- Author
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Raitano S, Ordovàs L, De Muynck L, Guo W, Espuny-Camacho I, Geraerts M, Khurana S, Vanuytsel K, Tóth BI, Voets T, Vandenberghe R, Cathomen T, Van Den Bosch L, Vanderhaeghen P, Van Damme P, and Verfaillie CM
- Subjects
- Biomarkers, Cell Differentiation, Cell Line, Frontotemporal Dementia therapy, Gene Expression Profiling, Haploinsufficiency, Humans, Induced Pluripotent Stem Cells cytology, Intercellular Signaling Peptides and Proteins metabolism, Mutation, Neural Stem Cells cytology, Neural Stem Cells metabolism, Phenotype, Progranulins, Time Factors, Transcription, Genetic, Transcriptome, Wnt Signaling Pathway, Frontotemporal Dementia genetics, Frontotemporal Dementia metabolism, Gene Expression, Induced Pluripotent Stem Cells metabolism, Intercellular Signaling Peptides and Proteins genetics, Neurogenesis genetics, Neurons metabolism
- Abstract
To understand how haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSCs) from patients carrying the GRN(IVS1+5G > C) mutation (FTD-iPSCs). FTD-iPSCs were fated to cortical neurons, the cells most affected in FTD. Although generation of neuroprogenitors was unaffected, their further differentiation into CTIP2-, FOXP2-, or TBR1-TUJ1 double-positive cortical neurons, but not motorneurons, was significantly decreased in FTD-neural progeny. Zinc finger nuclease-mediated introduction of GRN cDNA into the AAVS1 locus corrected defects in cortical neurogenesis, demonstrating that PGRN haploinsufficiency causes inefficient cortical neuron generation. RNA sequencing analysis confirmed reversal of the altered gene expression profile following genetic correction. We identified the Wnt signaling pathway as one of the top defective pathways in FTD-iPSC-derived neurons, which was reversed following genetic correction. Differentiation of FTD-iPSCs in the presence of a WNT inhibitor mitigated defective corticogenesis. Therefore, we demonstrate that PGRN haploinsufficiency hampers corticogenesis in vitro., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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