Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia

• Published in: Stem cell reports Vol. 4; no. 1; pp. 16 - 24
• Main Authors: Raitano, Susanna, Ordovàs, Laura, De Muynck, Louis, Guo, Wenting, Espuny-Camacho, Ira, Geraerts, Martine, Khurana, Satish, Vanuytsel, Kim, Tóth, Balazs I, Voets, Thomas, Vandenberghe, Rik, Cathomen, Toni, Van Den Bosch, Ludo, Vanderhaeghen, Pierre, Van Damme, Philip, Verfaillie, Catherine M
• Format: Journal Article
• Language: English
• Published: United States Elsevier 13.01.2015
• Subjects: Biomarkers; Cell Differentiation; Cell Line; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - therapy; Gene Expression; Gene Expression Profiling; Haploinsufficiency; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Mutation; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis - genetics; Neurons - metabolism; Phenotype; Progranulins; Time Factors; Transcription, Genetic; Transcriptome; Wnt Signaling Pathway
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.12.001

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.