title: Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia.
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.
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Susanna
authors.initials: S
authors.lastname: Raitano
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Ordovàs
authors.affiliation: Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: De Muynck
authors.affiliation: Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium.
authors.forename: Wenting
authors.initials: W
authors.lastname: Guo
authors.affiliation: Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Ira
authors.initials: I
authors.lastname: Espuny-Camacho
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Geraerts
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Satish
authors.initials: S
authors.lastname: Khurana
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Vanuytsel
authors.affiliation: Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Balazs I
authors.initials: BI
authors.lastname: Tóth
authors.affiliation: Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.affiliation: Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Institute for Cell and Gene Therapy, University Medical Center, 79108 Freiburg, Germany; Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Cathomen
authors.affiliation: Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.affiliation: Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium; VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanderhaeghen
authors.affiliation: Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium; Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium; Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium; Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium. Electronic address: catherine.verfaillie@med.kuleuven.be.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
mesh_terms: D015415:Biomarkers; D002454:Cell Differentiation; D002460:Cell Line; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D015870:Gene Expression; D020869:Gene Expression Profiling; D057895:Haploinsufficiency; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D000077153:Progranulins; D013997:Time Factors; D014158:Transcription, Genetic; D059467:Transcriptome; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins