Restoration of progranulin expression rescues cortical neuron generation in induced pluripotent stem cell model of frontotemporal dementia by mitigating increased WNT signaling
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Raitano, S; KU Leuven, 3000 Leuven, Belgium > Stem Cell Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration
Ordovàs, L; KU Leuven, 3000 Leuven, Belgium > Stem Cell Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration
De Muynck, K; VIB, Leuven, Belgium, KU Leuven, Leuven, Belgium > Leuven Research IVIB Vesalius Research Center, Research Group Experimental Neurology, Department of Neurosciences, Laboratory of Neurobiology
Guo, W; VIB, Leuven, Belgium, KU Leuven, Leuven, Belgium > VIB Vesalius Research Center, Research Group Experimental Neurology, Department of Neurosciences, Laboratory of Neurobiology
Espuny Camacho, Ira Mercedes ; Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium ; VIB Center for the Biology of Disease, 3000 Leuven, Belgium > Institute for Interdisciplinary Research (IRIBHM), Center of Human Genetics
Geraerts, M; KU Leuven, 3000 Leuven, Belgium > Stem Cell Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration
Khurana, S; KU Leuven, 3000 Leuven, Belgium > Stem Cell Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration
Vanuytsel, K; KU Leuven, 3000 Leuven, Belgium > Stem Cell Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration
Tóth, BI; KU Leuven, 3000 Leuven, Belgium > Laboratory of Ion Channel Research
Voets, T; KU Leuven, 3000 Leuven, Belgium > Laboratory of Ion Channel Research
Vandenberghe, R; KU Leuven, 3000 Leuven, Belgium ; University Hospitals Leuven, 3000 Leuven, Belgium > Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium ; Department of Neurology,
Cathomen, T; University Medical Center, 79108 Freiburg, Germany ; University Medical Center, 79108 Freiburg, Germany > Institute for Cell and Gene Therapy, Center for Chronic Immunodeficiency
Van Den Bosch; VIB, Leuven, Belgium, KU Leuven, Leuven, Belgium > VIB Vesalius Research Center, Research Group Experimental Neurology, Department of Neurosciences, Laboratory of Neurobiology
Vanderhaeghen, P; Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium ; VIB Center for the Biology of Disease, 3000 Leuven, Belgium > Institute for Interdisciplinary Research (IRIBHM), Center of Human Genetics
Van Damme, P; KU Leuven, 3000 Leuven, Belgium ; University Hospitals Leuven, 3000 Leuven, Belgium > Research Group Experimental Neurology, Department of Neurosciences, Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium ; Department of Neurology,
Verfaille, CM; KU Leuven, 3000 Leuven, Belgium > Stem Cell Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration
Restoration of progranulin expression rescues cortical neuron generation in induced pluripotent stem cell model of frontotemporal dementia by mitigating increased WNT signaling
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