Restoration of Progranulin Expression Rescues Cortical Neuron Generation in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia
Identifieur interne : 000183 ( Pmc/Checkpoint ); précédent : 000182; suivant : 000184Restoration of Progranulin Expression Rescues Cortical Neuron Generation in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia
Auteurs : Susanna Raitano [Belgique] ; Laura Ordovàs [Belgique] ; Louis De Muynck [Belgique] ; Wenting Guo [Belgique] ; Ira Espuny-Camacho [Belgique] ; Martine Geraerts [Belgique] ; Satish Khurana [Belgique] ; Kim Vanuytsel [Belgique] ; Balazs I. T Th [Belgique] ; Thomas Voets [Belgique] ; Rik Vandenberghe [Belgique] ; Toni Cathomen [Allemagne] ; Ludo Van Den Bosch [Belgique] ; Pierre Vanderhaeghen [Belgique] ; Philip Van Damme [Belgique] ; Catherine M. Verfaillie [Belgique]Source :
- Stem Cell Reports [ 2213-6711 ] ; 2014.
Abstract
To understand how haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSCs) from patients carrying the
Url:
DOI: 10.1016/j.stemcr.2014.12.001
PubMed: 25556567
PubMed Central: 4297877
Affiliations:
- Allemagne, Belgique
- Bade-Wurtemberg, District de Fribourg-en-Brisgau, Province du Brabant flamand, Vienne (Autriche)
- Fribourg-en-Brisgau, Louvain, Vienne (Autriche)
- Université libre de Bruxelles
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<author><name sortKey="Espuny Camacho, Ira" sort="Espuny Camacho, Ira" uniqKey="Espuny Camacho I" first="Ira" last="Espuny-Camacho">Ira Espuny-Camacho</name>
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<author><name sortKey="Geraerts, Martine" sort="Geraerts, Martine" uniqKey="Geraerts M" first="Martine" last="Geraerts">Martine Geraerts</name>
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<author><name sortKey="Khurana, Satish" sort="Khurana, Satish" uniqKey="Khurana S" first="Satish" last="Khurana">Satish Khurana</name>
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<author><name sortKey="Vanuytsel, Kim" sort="Vanuytsel, Kim" uniqKey="Vanuytsel K" first="Kim" last="Vanuytsel">Kim Vanuytsel</name>
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<author><name sortKey="T Th, Balazs I" sort="T Th, Balazs I" uniqKey="T Th B" first="Balazs I." last="T Th">Balazs I. T Th</name>
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<author><name sortKey="Voets, Thomas" sort="Voets, Thomas" uniqKey="Voets T" first="Thomas" last="Voets">Thomas Voets</name>
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<author><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name>
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<affiliation wicri:level="3"><nlm:aff id="aff14">Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff>
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<author><name sortKey="Cathomen, Toni" sort="Cathomen, Toni" uniqKey="Cathomen T" first="Toni" last="Cathomen">Toni Cathomen</name>
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<affiliation wicri:level="3"><nlm:aff id="aff12">Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg, Germany</nlm:aff>
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<wicri:regionArea>Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg</wicri:regionArea>
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<author><name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name>
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<affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</nlm:aff>
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<author><name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
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<wicri:regionArea>Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels</wicri:regionArea>
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<wicri:regionArea>Institute of Neuroscience (UNI), ULB, 1070 Brussels</wicri:regionArea>
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<affiliation wicri:level="3"><nlm:aff id="aff8">VIB Center for the Biology of Disease, 3000 Leuven, Belgium</nlm:aff>
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<affiliation wicri:level="3"><nlm:aff id="aff13">Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels</wicri:regionArea>
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<author><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name>
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<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
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<affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
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<affiliation wicri:level="3"><nlm:aff id="aff14">Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Neurology, University Hospitals Leuven, 3000 Leuven</wicri:regionArea>
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<settlement type="city">Louvain</settlement>
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</author>
<author><name sortKey="Verfaillie, Catherine M" sort="Verfaillie, Catherine M" uniqKey="Verfaillie C" first="Catherine M." last="Verfaillie">Catherine M. Verfaillie</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
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</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">25556567</idno>
<idno type="pmc">4297877</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297877</idno>
<idno type="RBID">PMC:4297877</idno>
<idno type="doi">10.1016/j.stemcr.2014.12.001</idno>
<date when="2014">2014</date>
<idno type="wicri:Area/Pmc/Corpus">000261</idno>
<idno type="wicri:Area/Pmc/Curation">000261</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000183</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Restoration of Progranulin Expression Rescues Cortical Neuron Generation in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia</title>
<author><name sortKey="Raitano, Susanna" sort="Raitano, Susanna" uniqKey="Raitano S" first="Susanna" last="Raitano">Susanna Raitano</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ordovas, Laura" sort="Ordovas, Laura" uniqKey="Ordovas L" first="Laura" last="Ordovàs">Laura Ordovàs</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="De Muynck, Louis" sort="De Muynck, Louis" uniqKey="De Muynck L" first="Louis" last="De Muynck">Louis De Muynck</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Guo, Wenting" sort="Guo, Wenting" uniqKey="Guo W" first="Wenting" last="Guo">Wenting Guo</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Espuny Camacho, Ira" sort="Espuny Camacho, Ira" uniqKey="Espuny Camacho I" first="Ira" last="Espuny-Camacho">Ira Espuny-Camacho</name>
<affiliation wicri:level="4"><nlm:aff id="aff6">Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels</wicri:regionArea>
<placeName><region type="land" nuts="2">Vienne (Autriche)</region>
<settlement type="city">Vienne (Autriche)</settlement>
</placeName>
<orgName type="university">Université libre de Bruxelles</orgName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff7">Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Institute of Neuroscience (UNI), ULB, 1070 Brussels</wicri:regionArea>
<placeName><region type="land" nuts="2">Vienne (Autriche)</region>
<settlement type="city">Vienne (Autriche)</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff8">VIB Center for the Biology of Disease, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>VIB Center for the Biology of Disease, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff9">Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Center of Human Genetics, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Geraerts, Martine" sort="Geraerts, Martine" uniqKey="Geraerts M" first="Martine" last="Geraerts">Martine Geraerts</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Khurana, Satish" sort="Khurana, Satish" uniqKey="Khurana S" first="Satish" last="Khurana">Satish Khurana</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vanuytsel, Kim" sort="Vanuytsel, Kim" uniqKey="Vanuytsel K" first="Kim" last="Vanuytsel">Kim Vanuytsel</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="T Th, Balazs I" sort="T Th, Balazs I" uniqKey="T Th B" first="Balazs I." last="T Th">Balazs I. T Th</name>
<affiliation wicri:level="3"><nlm:aff id="aff10">Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Voets, Thomas" sort="Voets, Thomas" uniqKey="Voets T" first="Thomas" last="Voets">Thomas Voets</name>
<affiliation wicri:level="3"><nlm:aff id="aff10">Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff14">Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Neurology, University Hospitals Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cathomen, Toni" sort="Cathomen, Toni" uniqKey="Cathomen T" first="Toni" last="Cathomen">Toni Cathomen</name>
<affiliation wicri:level="3"><nlm:aff id="aff11">Institute for Cell and Gene Therapy, University Medical Center, 79108 Freiburg, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute for Cell and Gene Therapy, University Medical Center, 79108 Freiburg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Fribourg-en-Brisgau</region>
<settlement type="city">Fribourg-en-Brisgau</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff12">Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Fribourg-en-Brisgau</region>
<settlement type="city">Fribourg-en-Brisgau</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
<affiliation wicri:level="4"><nlm:aff id="aff6">Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels</wicri:regionArea>
<placeName><region type="land" nuts="2">Vienne (Autriche)</region>
<settlement type="city">Vienne (Autriche)</settlement>
</placeName>
<orgName type="university">Université libre de Bruxelles</orgName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff7">Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Institute of Neuroscience (UNI), ULB, 1070 Brussels</wicri:regionArea>
<placeName><region type="land" nuts="2">Vienne (Autriche)</region>
<settlement type="city">Vienne (Autriche)</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff8">VIB Center for the Biology of Disease, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>VIB Center for the Biology of Disease, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff9">Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Center of Human Genetics, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff13">Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels</wicri:regionArea>
<placeName><region type="land" nuts="2">Vienne (Autriche)</region>
<settlement type="city">Vienne (Autriche)</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff14">Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Neurology, University Hospitals Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Verfaillie, Catherine M" sort="Verfaillie, Catherine M" uniqKey="Verfaillie C" first="Catherine M." last="Verfaillie">Catherine M. Verfaillie</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Institute, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven</wicri:regionArea>
<placeName><region type="province" nuts="2">Province du Brabant flamand</region>
<settlement type="city">Louvain</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Stem Cell Reports</title>
<idno type="eISSN">2213-6711</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><title>Summary</title>
<p>To understand how haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSCs) from patients carrying the <italic>GRN</italic>
<sup>IVS1+5G > C</sup>
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 <italic>GRN</italic>
cDNA into the <italic>AAVS1</italic>
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.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Almeida, S" uniqKey="Almeida S">S. Almeida</name>
</author>
<author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z. Zhang</name>
</author>
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<pmc article-type="brief-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Stem Cell Reports</journal-id>
<journal-id journal-id-type="iso-abbrev">Stem Cell Reports</journal-id>
<journal-title-group><journal-title>Stem Cell Reports</journal-title>
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<issn pub-type="epub">2213-6711</issn>
<publisher><publisher-name>Elsevier</publisher-name>
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<article-meta><article-id pub-id-type="pmid">25556567</article-id>
<article-id pub-id-type="pmc">4297877</article-id>
<article-id pub-id-type="publisher-id">S2213-6711(14)00358-0</article-id>
<article-id pub-id-type="doi">10.1016/j.stemcr.2014.12.001</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Report</subject>
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<title-group><article-title>Restoration of Progranulin Expression Rescues Cortical Neuron Generation in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia</article-title>
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<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guo</surname>
<given-names>Wenting</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
<xref rid="aff4" ref-type="aff">4</xref>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Espuny-Camacho</surname>
<given-names>Ira</given-names>
</name>
<xref rid="aff6" ref-type="aff">6</xref>
<xref rid="aff7" ref-type="aff">7</xref>
<xref rid="aff8" ref-type="aff">8</xref>
<xref rid="aff9" ref-type="aff">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Geraerts</surname>
<given-names>Martine</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Khurana</surname>
<given-names>Satish</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vanuytsel</surname>
<given-names>Kim</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tóth</surname>
<given-names>Balazs I.</given-names>
</name>
<xref rid="aff10" ref-type="aff">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Voets</surname>
<given-names>Thomas</given-names>
</name>
<xref rid="aff10" ref-type="aff">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vandenberghe</surname>
<given-names>Rik</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
<xref rid="aff4" ref-type="aff">4</xref>
<xref rid="aff14" ref-type="aff">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cathomen</surname>
<given-names>Toni</given-names>
</name>
<xref rid="aff11" ref-type="aff">11</xref>
<xref rid="aff12" ref-type="aff">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Van Den Bosch</surname>
<given-names>Ludo</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
<xref rid="aff4" ref-type="aff">4</xref>
<xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vanderhaeghen</surname>
<given-names>Pierre</given-names>
</name>
<xref rid="aff6" ref-type="aff">6</xref>
<xref rid="aff7" ref-type="aff">7</xref>
<xref rid="aff8" ref-type="aff">8</xref>
<xref rid="aff9" ref-type="aff">9</xref>
<xref rid="aff13" ref-type="aff">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Van Damme</surname>
<given-names>Philip</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
<xref rid="aff4" ref-type="aff">4</xref>
<xref rid="aff5" ref-type="aff">5</xref>
<xref rid="aff14" ref-type="aff">14</xref>
<xref rid="fn1" ref-type="fn">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Verfaillie</surname>
<given-names>Catherine M.</given-names>
</name>
<email>catherine.verfaillie@med.kuleuven.be</email>
<xref rid="aff1" ref-type="aff">1</xref>
<xref rid="aff2" ref-type="aff">2</xref>
<xref rid="fn1" ref-type="fn">15</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium</aff>
<aff id="aff2"><label>2</label>
Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium</aff>
<aff id="aff3"><label>3</label>
Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, 3000 Leuven, Belgium</aff>
<aff id="aff4"><label>4</label>
Research Group Experimental Neurology, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium</aff>
<aff id="aff5"><label>5</label>
Laboratory of Neurobiology, VIB Vesalius Research Center, 3000 Leuven, Belgium</aff>
<aff id="aff6"><label>6</label>
Institute for Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium</aff>
<aff id="aff7"><label>7</label>
Institute of Neuroscience (UNI), ULB, 1070 Brussels, Belgium</aff>
<aff id="aff8"><label>8</label>
VIB Center for the Biology of Disease, 3000 Leuven, Belgium</aff>
<aff id="aff9"><label>9</label>
Center of Human Genetics, KU Leuven, 3000 Leuven, Belgium</aff>
<aff id="aff10"><label>10</label>
Laboratory of Ion Channel Research, KU Leuven, 3000 Leuven, Belgium</aff>
<aff id="aff11"><label>11</label>
Institute for Cell and Gene Therapy, University Medical Center, 79108 Freiburg, Germany</aff>
<aff id="aff12"><label>12</label>
Center for Chronic Immunodeficiency, University Medical Center, 79108 Freiburg, Germany</aff>
<aff id="aff13"><label>13</label>
Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1070 Brussels, Belgium</aff>
<aff id="aff14"><label>14</label>
Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author <email>catherine.verfaillie@med.kuleuven.be</email>
</corresp>
<fn id="fn1"><label>15</label>
<p>Co-senior author</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release"><day>31</day>
<month>12</month>
<year>2014</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>31</day>
<month>12</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="collection"><day>13</day>
<month>1</month>
<year>2015</year>
</pub-date>
<volume>4</volume>
<issue>1</issue>
<fpage>16</fpage>
<lpage>24</lpage>
<history><date date-type="received"><day>4</day>
<month>7</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>28</day>
<month>11</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>1</day>
<month>12</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2015 The Authors</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).</license-p>
</license>
</permissions>
<abstract><title>Summary</title>
<p>To understand how haploinsufficiency of progranulin (PGRN) causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSCs) from patients carrying the <italic>GRN</italic>
<sup>IVS1+5G > C</sup>
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 <italic>GRN</italic>
cDNA into the <italic>AAVS1</italic>
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.</p>
</abstract>
<abstract abstract-type="graphical"><title>Graphical Abstract</title>
<fig id="undfig1" position="anchor"><graphic xlink:href="fx1"></graphic>
</fig>
</abstract>
<abstract abstract-type="author-highlights"><title>Highlights</title>
<p><list list-type="simple"><list-item id="u0010"><label>•</label>
<p>In vitro generation of cortical neurons from PGRN deficient FTD-iPSC is inefficient</p>
</list-item>
<list-item id="u0015"><label>•</label>
<p>Incorporation of <italic>GRN</italic>
cDNA via ZFN technology rescues cortical neurons generation</p>
</list-item>
<list-item id="u0020"><label>•</label>
<p>WNT signaling may also play a major role in the defects observed</p>
</list-item>
</list>
</p>
</abstract>
<abstract abstract-type="teaser"><p>Verfaillie and colleagues describe the inefficient cortical neuron, but not motorneuron, generation, from FTD-patient-derived iPSCs carrying a mutation in the <italic>GRN</italic>
gene. They show restoration of the defective phenotype following introduction of the <italic>GRN</italic>
cDNA in FTD-iPSC using zinc finger nucleases and by inhibiting the WNT pathway.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="fig1"><label>Figure 1</label>
<caption><p>Generation of Cortical Neurons from FTD-iPSCs and CTRL Lines</p>
<p>(A) <italic>GRN</italic>
levels in FTD-iPSC lines compared to those in control CTRL-iPSC lines (n = 3 independent experiments). Error bars indicate mean ± SEM. <sup>∗</sup>
p < 0.05, t test.</p>
<p>(B) <italic>CTIP</italic>
and <italic>FOXG1</italic>
expression in d40 progeny of FTD-iPSC and CTRL lines (n = 3 independent experiments). Error bars indicate mean ± SEM. <sup>∗</sup>
p < 0.05, t test.</p>
<p>(C) Immunostaining for TUJ1 and the cortical markers TBR1, CTIP2, and FOXP2. FTD1#1-iPSC and CTRL-iPSC progeny at d40 are shown. Scale bar, 100 μm.</p>
<p>(D) Enumeration of TUJ1-positive cells in FTD-iPSC and CTRL-iPSC d40 progeny. FTD1#1 and FTD3#6 (FTD) lines and CTRL-iPSC and H9-hESC (CTRL) lines are shown (n = 3 independent experiments per line. Error bars indicate mean ± SEM. <sup>∗</sup>
p < 0.05, t test.</p>
<p>(E) Immunostaining on d40 progeny for Nestin (n = 3). Scale bar, 100 μm.</p>
<p>(F) Immunostaining of FTD3#6 on d40 of differentiation to motorneurons for TUJ1, SMI32, HB9, and ISLET1 (n = 2). Scale bar, 100 μm.</p>
<p>See also <xref rid="app2" ref-type="sec">Figures S1</xref>
and <xref rid="app2" ref-type="sec">S2</xref>
.</p>
</caption>
<graphic xlink:href="gr1"></graphic>
</fig>
<fig id="fig2"><label>Figure 2</label>
<caption><p>Gene Targeting Using ZFNs</p>
<p>(A) Schematic representation of <italic>GRN</italic>
gene targeting in the <italic>AAVS1</italic>
locus. HA, homology arm; CAGGS, chicken β-actin promoter; HYG<sup>R</sup>
, hygromycin resistance-thymidine kinase fusion gene. Blue arrows, primers designed for junction assay (JA) PCR at the 5′ of the construct; red arrows, PCR for JA at the 3′. PURO<sup>R</sup>
, puromycin resistance.</p>
<p>(B) JA-PCR for several clones; the clone number 9 was selected. <bold>+</bold>
, positive control for 3′ JA (engineered H9-hESC line created by L.O. [unpublished data]); <bold>−</bold>
, negative control (FTD-iPSC not targeted).</p>
<p>(C) Southern blot of FTD3#6 and FTD3#6-PGRN lines.</p>
<p>(D) <italic>GRN</italic>
expression in FTD3#6, H9-hESC, FTD3#6-PGRN, and H9-PGRN lines (NS, not significant, p = 1.6, t test; n = 3 different passages). Error bars indicate mean ± SEM. <sup>#</sup>
p = 0.07; <sup>∗</sup>
p < 0.05, t test.</p>
<p>(E) <italic>NANOG</italic>
, <italic>OCT4</italic>
, and <italic>DPPA4</italic>
expression in FTD3#6, FTD3#6-PGRN, and H9-hESC lines (NS, not significant, p = 0.26, t test; n = 3 different passages). Error bars indicate mean ± SEM.</p>
<p>(F) Immunostaining of FTD3#6-PGRN for OCT4, SSEA4, and TRA1-60 (n = 3). Scale bar, 100 μm.</p>
<p>(G) FTD3#6-PGRN-derived teratoma with presence of derivatives of all three germ layers. Scale bar, 500 μm.</p>
<p>See also <xref rid="app2" ref-type="sec">Figure S3</xref>
.</p>
</caption>
<graphic xlink:href="gr2"></graphic>
</fig>
<fig id="fig3"><label>Figure 3</label>
<caption><p>Rescue of Corticogenesis in FTD3#6-PGRN Cells</p>
<p>(A) <italic>BLBP</italic>
, <italic>FOXG1</italic>
, and <italic>CTIP2</italic>
expression in FTD3#6-PGRN, FTD3#6-iPSC, H9-hESC, and H9-PGRN lines (n = 3 independent experiments). NS, not significant; p = 0.28, p = 0.23, p = 0.2 for top, middle, and bottom panels, respectively, t test. Error bars indicate mean ± SEM. <sup>∗</sup>
p < 0.05, t test.</p>
<p>(B) Immunostaining of FTD3#6 and FTD3#6-PGRN for TUJ1 and CTIP2, FOXP2, and TBR1 (n = 3). Scale bars, 100 μm.</p>
<p>(C) Enumeration of TUJ1-positive (I) and CTIP2-positive cells (II) in d40 progeny from FTD3#6-PGRN iPSCs compared to FTD3#6 and CTRL-iPSC lines (n = 3 independent experiments per line). Error bars indicate mean ± SEM. <sup>∗</sup>
p < 0.05, t test.</p>
<p>(D) Immunostaining of FTD3#6-PGRN for TUJ1 and HB9 (n = 2). Scale bar, 100 μm.</p>
<p>(E) Transcript levels of motorneuron precursor and mature markers (n = 2 independent experiments). Error bars indicate mean ± SEM.</p>
<p>See also <xref rid="app2" ref-type="sec">Figure S3</xref>
.</p>
</caption>
<graphic xlink:href="gr3"></graphic>
</fig>
<fig id="fig4"><label>Figure 4</label>
<caption><p>Genome-wide Transcriptome Analysis of d40 Neuronal Progeny</p>
<p>(A) Table with the significantly differentially expressed genes (using Benjamini-Hochberg-corrected p values).</p>
<p>(B) Represents the log fold change of gene transcripts of <italic>TUBB3</italic>
, <italic>TBR1</italic>
, <italic>FOXP2</italic>
, <italic>CTIP2</italic>
, <italic>FOXG1</italic>
, <italic>BLBP</italic>
, and <italic>MAP2</italic>
in d40 neural progeny of the FTD3#6, H9-hESC, and FTD3#6-PGRN lines from RNA-seq studies.</p>
<p>(C) Wnt signaling pathway, overlaid with the differentially expressed genes (log<sub>2</sub>
ratio >1 or <−1) of FTD3#6 versus H9-hESC line comparison. Upregulated genes are in green, and downregulated genes are in red.</p>
<p>(D) Western blot for active and total β-catenin on H9-hESCs at d24 treated with DMSO or DMSO-IWP2 (IWP2). β-actin, internal control.</p>
<p>(E) Panel I: Relative expression of <italic>BLBP</italic>
and <italic>FOXG1</italic>
transcripts in FTD3#6 treated with or without DMSO and IWP2 (n = 3 independent experiments). Error bars indicate mean ± SEM; <sup>∗</sup>
p < 0.05, t test. Panel II: <italic>BLBP</italic>
and <italic>FOXG1</italic>
transcripts in FTD3#6-iPSC treated with DMSO or DMSO-IWP2 (IWP2). n = 3 independent experiments. Error bars indicate mean ± SEM. <sup>∗</sup>
p < 0.05, t test.</p>
<p>(F) Immunostaining on FTD3#6 d40 progeny treated with DMSO-IWP2 (IWP2) for NESTIN and BLBP or TUJ1 and CTIP2 (n = 3). Scale bars, 100 μm.</p>
<p>See also <xref rid="app2" ref-type="sec">Figure S4</xref>
.</p>
</caption>
<graphic xlink:href="gr4"></graphic>
</fig>
</floats-group>
</pmc>
<affiliations><list><country><li>Allemagne</li>
<li>Belgique</li>
</country>
<region><li>Bade-Wurtemberg</li>
<li>District de Fribourg-en-Brisgau</li>
<li>Province du Brabant flamand</li>
<li>Vienne (Autriche)</li>
</region>
<settlement><li>Fribourg-en-Brisgau</li>
<li>Louvain</li>
<li>Vienne (Autriche)</li>
</settlement>
<orgName><li>Université libre de Bruxelles</li>
</orgName>
</list>
<tree><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Raitano, Susanna" sort="Raitano, Susanna" uniqKey="Raitano S" first="Susanna" last="Raitano">Susanna Raitano</name>
</region>
<name sortKey="De Muynck, Louis" sort="De Muynck, Louis" uniqKey="De Muynck L" first="Louis" last="De Muynck">Louis De Muynck</name>
<name sortKey="De Muynck, Louis" sort="De Muynck, Louis" uniqKey="De Muynck L" first="Louis" last="De Muynck">Louis De Muynck</name>
<name sortKey="De Muynck, Louis" sort="De Muynck, Louis" uniqKey="De Muynck L" first="Louis" last="De Muynck">Louis De Muynck</name>
<name sortKey="Espuny Camacho, Ira" sort="Espuny Camacho, Ira" uniqKey="Espuny Camacho I" first="Ira" last="Espuny-Camacho">Ira Espuny-Camacho</name>
<name sortKey="Espuny Camacho, Ira" sort="Espuny Camacho, Ira" uniqKey="Espuny Camacho I" first="Ira" last="Espuny-Camacho">Ira Espuny-Camacho</name>
<name sortKey="Espuny Camacho, Ira" sort="Espuny Camacho, Ira" uniqKey="Espuny Camacho I" first="Ira" last="Espuny-Camacho">Ira Espuny-Camacho</name>
<name sortKey="Espuny Camacho, Ira" sort="Espuny Camacho, Ira" uniqKey="Espuny Camacho I" first="Ira" last="Espuny-Camacho">Ira Espuny-Camacho</name>
<name sortKey="Geraerts, Martine" sort="Geraerts, Martine" uniqKey="Geraerts M" first="Martine" last="Geraerts">Martine Geraerts</name>
<name sortKey="Geraerts, Martine" sort="Geraerts, Martine" uniqKey="Geraerts M" first="Martine" last="Geraerts">Martine Geraerts</name>
<name sortKey="Guo, Wenting" sort="Guo, Wenting" uniqKey="Guo W" first="Wenting" last="Guo">Wenting Guo</name>
<name sortKey="Guo, Wenting" sort="Guo, Wenting" uniqKey="Guo W" first="Wenting" last="Guo">Wenting Guo</name>
<name sortKey="Guo, Wenting" sort="Guo, Wenting" uniqKey="Guo W" first="Wenting" last="Guo">Wenting Guo</name>
<name sortKey="Khurana, Satish" sort="Khurana, Satish" uniqKey="Khurana S" first="Satish" last="Khurana">Satish Khurana</name>
<name sortKey="Khurana, Satish" sort="Khurana, Satish" uniqKey="Khurana S" first="Satish" last="Khurana">Satish Khurana</name>
<name sortKey="Ordovas, Laura" sort="Ordovas, Laura" uniqKey="Ordovas L" first="Laura" last="Ordovàs">Laura Ordovàs</name>
<name sortKey="Ordovas, Laura" sort="Ordovas, Laura" uniqKey="Ordovas L" first="Laura" last="Ordovàs">Laura Ordovàs</name>
<name sortKey="Raitano, Susanna" sort="Raitano, Susanna" uniqKey="Raitano S" first="Susanna" last="Raitano">Susanna Raitano</name>
<name sortKey="T Th, Balazs I" sort="T Th, Balazs I" uniqKey="T Th B" first="Balazs I." last="T Th">Balazs I. T Th</name>
<name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name>
<name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name>
<name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name>
<name sortKey="Van Damme, Philip" sort="Van Damme, Philip" uniqKey="Van Damme P" first="Philip" last="Van Damme">Philip Van Damme</name>
<name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name>
<name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name>
<name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name>
<name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name>
<name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name>
<name sortKey="Vandenberghe, Rik" sort="Vandenberghe, Rik" uniqKey="Vandenberghe R" first="Rik" last="Vandenberghe">Rik Vandenberghe</name>
<name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
<name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
<name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
<name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
<name sortKey="Vanderhaeghen, Pierre" sort="Vanderhaeghen, Pierre" uniqKey="Vanderhaeghen P" first="Pierre" last="Vanderhaeghen">Pierre Vanderhaeghen</name>
<name sortKey="Vanuytsel, Kim" sort="Vanuytsel, Kim" uniqKey="Vanuytsel K" first="Kim" last="Vanuytsel">Kim Vanuytsel</name>
<name sortKey="Vanuytsel, Kim" sort="Vanuytsel, Kim" uniqKey="Vanuytsel K" first="Kim" last="Vanuytsel">Kim Vanuytsel</name>
<name sortKey="Verfaillie, Catherine M" sort="Verfaillie, Catherine M" uniqKey="Verfaillie C" first="Catherine M." last="Verfaillie">Catherine M. Verfaillie</name>
<name sortKey="Verfaillie, Catherine M" sort="Verfaillie, Catherine M" uniqKey="Verfaillie C" first="Catherine M." last="Verfaillie">Catherine M. Verfaillie</name>
<name sortKey="Voets, Thomas" sort="Voets, Thomas" uniqKey="Voets T" first="Thomas" last="Voets">Thomas Voets</name>
</country>
<country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Cathomen, Toni" sort="Cathomen, Toni" uniqKey="Cathomen T" first="Toni" last="Cathomen">Toni Cathomen</name>
</region>
<name sortKey="Cathomen, Toni" sort="Cathomen, Toni" uniqKey="Cathomen T" first="Toni" last="Cathomen">Toni Cathomen</name>
</country>
</tree>
</affiliations>
</record>
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