The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A
Identifieur interne : 000006 ( Pmc/Checkpoint ); précédent : 000005; suivant : 000007The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A
Auteurs : Inmaculada Segura [Belgique] ; Christian Lange [Belgique] ; Ellen Knevels [Belgique] ; Anastasiya Moskalyuk [Belgique] ; Rocco Pulizzi [Belgique] ; Guy Eelen [Belgique] ; Thibault Chaze [France] ; Cicerone Tudor [Belgique] ; Cyril Boulegue [France] ; Matthew Holt [Belgique] ; Dirk Daelemans [Belgique] ; Mariette Matondo [France] ; Bart Ghesquière [Belgique] ; Michele Giugliano [Belgique, Suisse] ; Carmen Ruiz De Almodovar [Belgique] ; Mieke Dewerchin [Belgique] ; Peter Carmeliet [Belgique]Source :
- Cell Reports [ 2211-1247 ] ; 2016.
Abstract
Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of
Url:
DOI: 10.1016/j.celrep.2016.02.047
PubMed: 26972007
PubMed Central: 4805856
Affiliations:
- Belgique, France, Suisse
- Canton de Vaud, Province d'Anvers, Province du Brabant flamand, Île-de-France
- Anvers, Heverlee, Lausanne, Louvain, Paris
- Université d'Anvers
Links toward previous steps (curation, corpus...)
Links to Exploration step
PMC:4805856Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A</title><author><name sortKey="Segura, Inmaculada" sort="Segura, Inmaculada" uniqKey="Segura I" first="Inmaculada" last="Segura">Inmaculada Segura</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Lange, Christian" sort="Lange, Christian" uniqKey="Lange C" first="Christian" last="Lange">Christian Lange</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Knevels, Ellen" sort="Knevels, Ellen" uniqKey="Knevels E" first="Ellen" last="Knevels">Ellen Knevels</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Moskalyuk, Anastasiya" sort="Moskalyuk, Anastasiya" uniqKey="Moskalyuk A" first="Anastasiya" last="Moskalyuk">Anastasiya Moskalyuk</name><affiliation wicri:level="4"><nlm:aff id="aff3">Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Pulizzi, Rocco" sort="Pulizzi, Rocco" uniqKey="Pulizzi R" first="Rocco" last="Pulizzi">Rocco Pulizzi</name><affiliation wicri:level="4"><nlm:aff id="aff3">Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Eelen, Guy" sort="Eelen, Guy" uniqKey="Eelen G" first="Guy" last="Eelen">Guy Eelen</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Chaze, Thibault" sort="Chaze, Thibault" uniqKey="Chaze T" first="Thibault" last="Chaze">Thibault Chaze</name><affiliation wicri:level="3"><nlm:aff id="aff4">Proteomics Platform, Institute Pasteur, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Proteomics Platform, Institute Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Tudor, Cicerone" sort="Tudor, Cicerone" uniqKey="Tudor C" first="Cicerone" last="Tudor">Cicerone Tudor</name><affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Glia Biology, VIB, 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="Boulegue, Cyril" sort="Boulegue, Cyril" uniqKey="Boulegue C" first="Cyril" last="Boulegue">Cyril Boulegue</name><affiliation wicri:level="3"><nlm:aff id="aff4">Proteomics Platform, Institute Pasteur, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Proteomics Platform, Institute Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Holt, Matthew" sort="Holt, Matthew" uniqKey="Holt M" first="Matthew" last="Holt">Matthew Holt</name><affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Glia Biology, VIB, 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="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name><affiliation wicri:level="3"><nlm:aff id="aff6">Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Virology and Chemotherapy, Rega 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></author><author><name sortKey="Matondo, Mariette" sort="Matondo, Mariette" uniqKey="Matondo M" first="Mariette" last="Matondo">Mariette Matondo</name><affiliation wicri:level="3"><nlm:aff id="aff4">Proteomics Platform, Institute Pasteur, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Proteomics Platform, Institute Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Ghesquiere, Bart" sort="Ghesquiere, Bart" uniqKey="Ghesquiere B" first="Bart" last="Ghesquière">Bart Ghesquière</name><affiliation wicri:level="3"><nlm:aff id="aff7">Metabolomics Core Facility, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Metabolomics Core Facility, Vesalius Research Center, VIB, 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="Giugliano, Michele" sort="Giugliano, Michele" uniqKey="Giugliano M" first="Michele" last="Giugliano">Michele Giugliano</name><affiliation wicri:level="4"><nlm:aff id="aff3">Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff8">Neuro-Electronics Research Flanders, 3001 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Neuro-Electronics Research Flanders, 3001 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9">Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Ruiz De Almodovar, Carmen" sort="Ruiz De Almodovar, Carmen" uniqKey="Ruiz De Almodovar C" first="Carmen" last="Ruiz De Almodovar">Carmen Ruiz De Almodovar</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Dewerchin, Mieke" sort="Dewerchin, Mieke" uniqKey="Dewerchin M" first="Mieke" last="Dewerchin">Mieke Dewerchin</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26972007</idno><idno type="pmc">4805856</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805856</idno><idno type="RBID">PMC:4805856</idno><idno type="doi">10.1016/j.celrep.2016.02.047</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000347</idno><idno type="wicri:Area/Pmc/Curation">000347</idno><idno type="wicri:Area/Pmc/Checkpoint">000006</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A</title><author><name sortKey="Segura, Inmaculada" sort="Segura, Inmaculada" uniqKey="Segura I" first="Inmaculada" last="Segura">Inmaculada Segura</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Lange, Christian" sort="Lange, Christian" uniqKey="Lange C" first="Christian" last="Lange">Christian Lange</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Knevels, Ellen" sort="Knevels, Ellen" uniqKey="Knevels E" first="Ellen" last="Knevels">Ellen Knevels</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Moskalyuk, Anastasiya" sort="Moskalyuk, Anastasiya" uniqKey="Moskalyuk A" first="Anastasiya" last="Moskalyuk">Anastasiya Moskalyuk</name><affiliation wicri:level="4"><nlm:aff id="aff3">Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Pulizzi, Rocco" sort="Pulizzi, Rocco" uniqKey="Pulizzi R" first="Rocco" last="Pulizzi">Rocco Pulizzi</name><affiliation wicri:level="4"><nlm:aff id="aff3">Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation></author><author><name sortKey="Eelen, Guy" sort="Eelen, Guy" uniqKey="Eelen G" first="Guy" last="Eelen">Guy Eelen</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Chaze, Thibault" sort="Chaze, Thibault" uniqKey="Chaze T" first="Thibault" last="Chaze">Thibault Chaze</name><affiliation wicri:level="3"><nlm:aff id="aff4">Proteomics Platform, Institute Pasteur, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Proteomics Platform, Institute Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Tudor, Cicerone" sort="Tudor, Cicerone" uniqKey="Tudor C" first="Cicerone" last="Tudor">Cicerone Tudor</name><affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Glia Biology, VIB, 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="Boulegue, Cyril" sort="Boulegue, Cyril" uniqKey="Boulegue C" first="Cyril" last="Boulegue">Cyril Boulegue</name><affiliation wicri:level="3"><nlm:aff id="aff4">Proteomics Platform, Institute Pasteur, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Proteomics Platform, Institute Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Holt, Matthew" sort="Holt, Matthew" uniqKey="Holt M" first="Matthew" last="Holt">Matthew Holt</name><affiliation wicri:level="3"><nlm:aff id="aff5">Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Glia Biology, VIB, 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="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name><affiliation wicri:level="3"><nlm:aff id="aff6">Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Virology and Chemotherapy, Rega 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></author><author><name sortKey="Matondo, Mariette" sort="Matondo, Mariette" uniqKey="Matondo M" first="Mariette" last="Matondo">Mariette Matondo</name><affiliation wicri:level="3"><nlm:aff id="aff4">Proteomics Platform, Institute Pasteur, 75015 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Proteomics Platform, Institute Pasteur, 75015 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Ghesquiere, Bart" sort="Ghesquiere, Bart" uniqKey="Ghesquiere B" first="Bart" last="Ghesquière">Bart Ghesquière</name><affiliation wicri:level="3"><nlm:aff id="aff7">Metabolomics Core Facility, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Metabolomics Core Facility, Vesalius Research Center, VIB, 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="Giugliano, Michele" sort="Giugliano, Michele" uniqKey="Giugliano M" first="Michele" last="Giugliano">Michele Giugliano</name><affiliation wicri:level="4"><nlm:aff id="aff3">Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk</wicri:regionArea><orgName type="university">Université d'Anvers</orgName><placeName><settlement type="city">Anvers</settlement><region type="district" nuts="2">Province d'Anvers</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="aff8">Neuro-Electronics Research Flanders, 3001 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Neuro-Electronics Research Flanders, 3001 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9">Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Ruiz De Almodovar, Carmen" sort="Ruiz De Almodovar, Carmen" uniqKey="Ruiz De Almodovar C" first="Carmen" last="Ruiz De Almodovar">Carmen Ruiz De Almodovar</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Dewerchin, Mieke" sort="Dewerchin, Mieke" uniqKey="Dewerchin M" first="Mieke" last="Dewerchin">Mieke Dewerchin</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><affiliation wicri:level="3"><nlm:aff id="aff1">Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 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">Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 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">Cell Reports</title><idno type="eISSN">2211-1247</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><p>Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of <italic>Phd2</italic> induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas <italic>Flna</italic> silencing rescues the immature spine phenotype induced by PHD2 inhibition.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Araya, R" uniqKey="Araya R">R. Araya</name></author><author><name sortKey="Jiang, J" uniqKey="Jiang J">J. Jiang</name></author><author><name sortKey="Eisenthal, K B" uniqKey="Eisenthal K">K.B. Eisenthal</name></author><author><name sortKey="Yuste, R" uniqKey="Yuste R">R. Yuste</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bolduc, F V" uniqKey="Bolduc F">F.V. Bolduc</name></author><author><name sortKey="Bell, K" uniqKey="Bell K">K. Bell</name></author><author><name sortKey="Rosenfelt, C" uniqKey="Rosenfelt C">C. Rosenfelt</name></author><author><name sortKey="Cox, H" uniqKey="Cox H">H. Cox</name></author><author><name sortKey="Tully, T" uniqKey="Tully T">T. Tully</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brown, C E" uniqKey="Brown C">C.E. Brown</name></author><author><name sortKey="Boyd, J D" uniqKey="Boyd J">J.D. Boyd</name></author><author><name sortKey="Murphy, T H" uniqKey="Murphy T">T.H. Murphy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cho, K O" uniqKey="Cho K">K.O. Cho</name></author><author><name sortKey="Hunt, C A" uniqKey="Hunt C">C.A. Hunt</name></author><author><name sortKey="Kennedy, M B" uniqKey="Kennedy M">M.B. Kennedy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Corcoran, A" uniqKey="Corcoran A">A. Corcoran</name></author><author><name sortKey="Kunze, R" uniqKey="Kunze R">R. Kunze</name></author><author><name sortKey="Harney, S C" uniqKey="Harney S">S.C. Harney</name></author><author><name sortKey="Breier, G" uniqKey="Breier G">G. Breier</name></author><author><name sortKey="Marti, H H" uniqKey="Marti H">H.H. Marti</name></author><author><name sortKey="O Onnor, J J" uniqKey="O Onnor J">J.J. O’Connor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Epstein, A C" uniqKey="Epstein A">A.C. Epstein</name></author><author><name sortKey="Gleadle, J M" uniqKey="Gleadle J">J.M. Gleadle</name></author><author><name sortKey="Mcneill, L A" uniqKey="Mcneill L">L.A. McNeill</name></author><author><name sortKey="Hewitson, K S" uniqKey="Hewitson K">K.S. Hewitson</name></author><author><name sortKey="O Ourke, J" uniqKey="O Ourke J">J. O’Rourke</name></author><author><name sortKey="Mole, D R" uniqKey="Mole D">D.R. Mole</name></author><author><name sortKey="Mukherji, M" uniqKey="Mukherji M">M. Mukherji</name></author><author><name sortKey="Metzen, E" uniqKey="Metzen E">E. Metzen</name></author><author><name sortKey="Wilson, M I" uniqKey="Wilson M">M.I. Wilson</name></author><author><name sortKey="Dhanda, A" uniqKey="Dhanda A">A. Dhanda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ereci Ska, M" uniqKey="Ereci Ska M">M. Erecińska</name></author><author><name sortKey="Silver, I A" uniqKey="Silver I">I.A. Silver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ethell, I M" uniqKey="Ethell I">I.M. Ethell</name></author><author><name sortKey="Pasquale, E B" uniqKey="Pasquale E">E.B. Pasquale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gaillard, S" uniqKey="Gaillard S">S. Gaillard</name></author><author><name sortKey="Bailly, Y" uniqKey="Bailly Y">Y. Bailly</name></author><author><name sortKey="Benoist, M" uniqKey="Benoist M">M. Benoist</name></author><author><name sortKey="Rakitina, T" uniqKey="Rakitina T">T. Rakitina</name></author><author><name sortKey="Kessler, J P" uniqKey="Kessler J">J.P. Kessler</name></author><author><name sortKey="Fronzaroli Molinieres, L" uniqKey="Fronzaroli Molinieres L">L. Fronzaroli-Molinières</name></author><author><name sortKey="Dargent, B" uniqKey="Dargent B">B. Dargent</name></author><author><name sortKey="Castets, F" uniqKey="Castets F">F. Castets</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gambazzi, L" uniqKey="Gambazzi L">L. Gambazzi</name></author><author><name sortKey="Gokce, O" uniqKey="Gokce O">O. Gokce</name></author><author><name sortKey="Seredenina, T" uniqKey="Seredenina T">T. Seredenina</name></author><author><name sortKey="Katsyuba, E" uniqKey="Katsyuba E">E. Katsyuba</name></author><author><name sortKey="Runne, H" uniqKey="Runne H">H. Runne</name></author><author><name sortKey="Markram, H" uniqKey="Markram H">H. Markram</name></author><author><name sortKey="Giugliano, M" uniqKey="Giugliano M">M. Giugliano</name></author><author><name sortKey="Luthi Carter, R" uniqKey="Luthi Carter R">R. Luthi-Carter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hotulainen, P" uniqKey="Hotulainen P">P. Hotulainen</name></author><author><name sortKey="Hoogenraad, C C" uniqKey="Hoogenraad C">C.C. Hoogenraad</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ivan, M" uniqKey="Ivan M">M. Ivan</name></author><author><name sortKey="Kondo, K" uniqKey="Kondo K">K. Kondo</name></author><author><name sortKey="Yang, H" uniqKey="Yang H">H. Yang</name></author><author><name sortKey="Kim, W" uniqKey="Kim W">W. Kim</name></author><author><name sortKey="Valiando, J" uniqKey="Valiando J">J. Valiando</name></author><author><name sortKey="Ohh, M" uniqKey="Ohh M">M. Ohh</name></author><author><name sortKey="Salic, A" uniqKey="Salic A">A. Salic</name></author><author><name sortKey="Asara, J M" uniqKey="Asara J">J.M. Asara</name></author><author><name sortKey="Lane, W S" uniqKey="Lane W">W.S. Lane</name></author><author><name sortKey="Kaelin, W G" uniqKey="Kaelin W">W.G. Kaelin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jaakkola, P" uniqKey="Jaakkola P">P. Jaakkola</name></author><author><name sortKey="Mole, D R" uniqKey="Mole D">D.R. Mole</name></author><author><name sortKey="Tian, Y M" uniqKey="Tian Y">Y.M. Tian</name></author><author><name sortKey="Wilson, M I" uniqKey="Wilson M">M.I. Wilson</name></author><author><name sortKey="Gielbert, J" uniqKey="Gielbert J">J. Gielbert</name></author><author><name sortKey="Gaskell, S J" uniqKey="Gaskell S">S.J. Gaskell</name></author><author><name sortKey="Von Kriegsheim, A" uniqKey="Von Kriegsheim A">A. von Kriegsheim</name></author><author><name sortKey="Hebestreit, H F" uniqKey="Hebestreit H">H.F. Hebestreit</name></author><author><name sortKey="Mukherji, M" uniqKey="Mukherji M">M. Mukherji</name></author><author><name sortKey="Schofield, C J" uniqKey="Schofield C">C.J. Schofield</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mazzone, M" uniqKey="Mazzone M">M. Mazzone</name></author><author><name sortKey="Dettori, D" uniqKey="Dettori D">D. Dettori</name></author><author><name sortKey="Leite De Oliveira, R" uniqKey="Leite De Oliveira R">R. Leite de Oliveira</name></author><author><name sortKey="Loges, S" uniqKey="Loges S">S. Loges</name></author><author><name sortKey="Schmidt, T" uniqKey="Schmidt T">T. Schmidt</name></author><author><name sortKey="Jonckx, B" uniqKey="Jonckx B">B. Jonckx</name></author><author><name sortKey="Tian, Y M" uniqKey="Tian Y">Y.M. Tian</name></author><author><name sortKey="Lanahan, A A" uniqKey="Lanahan A">A.A. Lanahan</name></author><author><name sortKey="Pollard, P" uniqKey="Pollard P">P. Pollard</name></author><author><name sortKey="Ruiz De Almodovar, C" uniqKey="Ruiz De Almodovar C">C. Ruiz de Almodovar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meller, R" uniqKey="Meller R">R. Meller</name></author><author><name sortKey="Thompson, S J" uniqKey="Thompson S">S.J. Thompson</name></author><author><name sortKey="Lusardi, T A" uniqKey="Lusardi T">T.A. Lusardi</name></author><author><name sortKey="Ordonez, A N" uniqKey="Ordonez A">A.N. Ordonez</name></author><author><name sortKey="Ashley, M D" uniqKey="Ashley M">M.D. Ashley</name></author><author><name sortKey="Jessick, V" uniqKey="Jessick V">V. Jessick</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W. Wang</name></author><author><name sortKey="Torrey, D J" uniqKey="Torrey D">D.J. Torrey</name></author><author><name sortKey="Henshall, D C" uniqKey="Henshall D">D.C. Henshall</name></author><author><name sortKey="Gafken, P R" uniqKey="Gafken P">P.R. Gafken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nakamura, F" uniqKey="Nakamura F">F. Nakamura</name></author><author><name sortKey="Stossel, T P" uniqKey="Stossel T">T.P. Stossel</name></author><author><name sortKey="Hartwig, J H" uniqKey="Hartwig J">J.H. Hartwig</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nestor, M W" uniqKey="Nestor M">M.W. Nestor</name></author><author><name sortKey="Cai, X" uniqKey="Cai X">X. Cai</name></author><author><name sortKey="Stone, M R" uniqKey="Stone M">M.R. Stone</name></author><author><name sortKey="Bloch, R J" uniqKey="Bloch R">R.J. Bloch</name></author><author><name sortKey="Thompson, S M" uniqKey="Thompson S">S.M. Thompson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Noam, Y" uniqKey="Noam Y">Y. Noam</name></author><author><name sortKey="Phan, L" uniqKey="Phan L">L. Phan</name></author><author><name sortKey="Mcclelland, S" uniqKey="Mcclelland S">S. McClelland</name></author><author><name sortKey="Manders, E M" uniqKey="Manders E">E.M. Manders</name></author><author><name sortKey="Ehrengruber, M U" uniqKey="Ehrengruber M">M.U. Ehrengruber</name></author><author><name sortKey="Wadman, W J" uniqKey="Wadman W">W.J. Wadman</name></author><author><name sortKey="Baram, T Z" uniqKey="Baram T">T.Z. Baram</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nwabuisi Heath, E" uniqKey="Nwabuisi Heath E">E. Nwabuisi-Heath</name></author><author><name sortKey="Ladu, M J" uniqKey="Ladu M">M.J. LaDu</name></author><author><name sortKey="Yu, C" uniqKey="Yu C">C. Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oruganty Das, A" uniqKey="Oruganty Das A">A. Oruganty-Das</name></author><author><name sortKey="Ng, T" uniqKey="Ng T">T. Ng</name></author><author><name sortKey="Udagawa, T" uniqKey="Udagawa T">T. Udagawa</name></author><author><name sortKey="Goh, E L" uniqKey="Goh E">E.L. Goh</name></author><author><name sortKey="Richter, J D" uniqKey="Richter J">J.D. Richter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pacary, E" uniqKey="Pacary E">E. Pacary</name></author><author><name sortKey="Haas, M A" uniqKey="Haas M">M.A. Haas</name></author><author><name sortKey="Wildner, H" uniqKey="Wildner H">H. Wildner</name></author><author><name sortKey="Azzarelli, R" uniqKey="Azzarelli R">R. Azzarelli</name></author><author><name sortKey="Bell, D M" uniqKey="Bell D">D.M. Bell</name></author><author><name sortKey="Abrous, D N" uniqKey="Abrous D">D.N. Abrous</name></author><author><name sortKey="Guillemot, F" uniqKey="Guillemot F">F. Guillemot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reinartz, S" uniqKey="Reinartz S">S. Reinartz</name></author><author><name sortKey="Biro, I" uniqKey="Biro I">I. Biro</name></author><author><name sortKey="Gal, A" uniqKey="Gal A">A. Gal</name></author><author><name sortKey="Giugliano, M" uniqKey="Giugliano M">M. Giugliano</name></author><author><name sortKey="Marom, S" uniqKey="Marom S">S. Marom</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sarkisian, M R" uniqKey="Sarkisian M">M.R. Sarkisian</name></author><author><name sortKey="Bartley, C M" uniqKey="Bartley C">C.M. Bartley</name></author><author><name sortKey="Chi, H" uniqKey="Chi H">H. Chi</name></author><author><name sortKey="Nakamura, F" uniqKey="Nakamura F">F. Nakamura</name></author><author><name sortKey="Hashimoto Torii, K" uniqKey="Hashimoto Torii K">K. Hashimoto-Torii</name></author><author><name sortKey="Torii, M" uniqKey="Torii M">M. Torii</name></author><author><name sortKey="Flavell, R A" uniqKey="Flavell R">R.A. Flavell</name></author><author><name sortKey="Rakic, P" uniqKey="Rakic P">P. Rakic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Segura, I" uniqKey="Segura I">I. Segura</name></author><author><name sortKey="Essmann, C L" uniqKey="Essmann C">C.L. Essmann</name></author><author><name sortKey="Weinges, S" uniqKey="Weinges S">S. Weinges</name></author><author><name sortKey="Acker Palmer, A" uniqKey="Acker Palmer A">A. Acker-Palmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, D" uniqKey="Song D">D. Song</name></author><author><name sortKey="Li, L S" uniqKey="Li L">L.S. Li</name></author><author><name sortKey="Heaton Johnson, K J" uniqKey="Heaton Johnson K">K.J. Heaton-Johnson</name></author><author><name sortKey="Arsenault, P R" uniqKey="Arsenault P">P.R. Arsenault</name></author><author><name sortKey="Master, S R" uniqKey="Master S">S.R. Master</name></author><author><name sortKey="Lee, F S" uniqKey="Lee F">F.S. Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stossel, T P" uniqKey="Stossel T">T.P. Stossel</name></author><author><name sortKey="Condeelis, J" uniqKey="Condeelis J">J. Condeelis</name></author><author><name sortKey="Cooley, L" uniqKey="Cooley L">L. Cooley</name></author><author><name sortKey="Hartwig, J H" uniqKey="Hartwig J">J.H. Hartwig</name></author><author><name sortKey="Noegel, A" uniqKey="Noegel A">A. Noegel</name></author><author><name sortKey="Schleicher, M" uniqKey="Schleicher M">M. Schleicher</name></author><author><name sortKey="Shapiro, S S" uniqKey="Shapiro S">S.S. Shapiro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tashiro, A" uniqKey="Tashiro A">A. Tashiro</name></author><author><name sortKey="Yuste, R" uniqKey="Yuste R">R. Yuste</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsuchiya, H" uniqKey="Tsuchiya H">H. Tsuchiya</name></author><author><name sortKey="Iseda, T" uniqKey="Iseda T">T. Iseda</name></author><author><name sortKey="Hino, O" uniqKey="Hino O">O. Hino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Der Flier, A" uniqKey="Van Der Flier A">A. van der Flier</name></author><author><name sortKey="Sonnenberg, A" uniqKey="Sonnenberg A">A. Sonnenberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vogel, S" uniqKey="Vogel S">S. Vogel</name></author><author><name sortKey="Wottawa, M" uniqKey="Wottawa M">M. Wottawa</name></author><author><name sortKey="Farhat, K" uniqKey="Farhat K">K. Farhat</name></author><author><name sortKey="Zieseniss, A" uniqKey="Zieseniss A">A. Zieseniss</name></author><author><name sortKey="Schnelle, M" uniqKey="Schnelle M">M. Schnelle</name></author><author><name sortKey="Le Huu, S" uniqKey="Le Huu S">S. Le-Huu</name></author><author><name sortKey="Von Ahlen, M" uniqKey="Von Ahlen M">M. von Ahlen</name></author><author><name sortKey="Malz, C" uniqKey="Malz C">C. Malz</name></author><author><name sortKey="Camenisch, G" uniqKey="Camenisch G">G. Camenisch</name></author><author><name sortKey="Katschinski, D M" uniqKey="Katschinski D">D.M. Katschinski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong, B W" uniqKey="Wong B">B.W. Wong</name></author><author><name sortKey="Kuchnio, A" uniqKey="Kuchnio A">A. Kuchnio</name></author><author><name sortKey="Bruning, U" uniqKey="Bruning U">U. Bruning</name></author><author><name sortKey="Carmeliet, P" uniqKey="Carmeliet P">P. Carmeliet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, J" uniqKey="Zhang J">J. Zhang</name></author><author><name sortKey="Neal, J" uniqKey="Neal J">J. Neal</name></author><author><name sortKey="Lian, G" uniqKey="Lian G">G. Lian</name></author><author><name sortKey="Shi, B" uniqKey="Shi B">B. Shi</name></author><author><name sortKey="Ferland, R J" uniqKey="Ferland R">R.J. Ferland</name></author><author><name sortKey="Sheen, V" uniqKey="Sheen V">V. Sheen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, J" uniqKey="Zhang J">J. Zhang</name></author><author><name sortKey="Neal, J" uniqKey="Neal J">J. Neal</name></author><author><name sortKey="Lian, G" uniqKey="Lian G">G. Lian</name></author><author><name sortKey="Hu, J" uniqKey="Hu J">J. Hu</name></author><author><name sortKey="Lu, J" uniqKey="Lu J">J. Lu</name></author><author><name sortKey="Sheen, V" uniqKey="Sheen V">V. Sheen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, L" uniqKey="Zhang L">L. Zhang</name></author><author><name sortKey="Bartley, C M" uniqKey="Bartley C">C.M. Bartley</name></author><author><name sortKey="Gong, X" uniqKey="Gong X">X. Gong</name></author><author><name sortKey="Hsieh, L S" uniqKey="Hsieh L">L.S. Hsieh</name></author><author><name sortKey="Lin, T V" uniqKey="Lin T">T.V. Lin</name></author><author><name sortKey="Feliciano, D M" uniqKey="Feliciano D">D.M. Feliciano</name></author><author><name sortKey="Bordey, A" uniqKey="Bordey A">A. Bordey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zheng, L" uniqKey="Zheng L">L. Zheng</name></author><author><name sortKey="Michelson, Y" uniqKey="Michelson Y">Y. Michelson</name></author><author><name sortKey="Freger, V" uniqKey="Freger V">V. Freger</name></author><author><name sortKey="Avraham, Z" uniqKey="Avraham Z">Z. Avraham</name></author><author><name sortKey="Venken, K J" uniqKey="Venken K">K.J. Venken</name></author><author><name sortKey="Bellen, H J" uniqKey="Bellen H">H.J. Bellen</name></author><author><name sortKey="Justice, M J" uniqKey="Justice M">M.J. Justice</name></author><author><name sortKey="Wides, R" uniqKey="Wides R">R. Wides</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zheng, X" uniqKey="Zheng X">X. Zheng</name></author><author><name sortKey="Zhou, A X" uniqKey="Zhou A">A.X. Zhou</name></author><author><name sortKey="Rouhi, P" uniqKey="Rouhi P">P. Rouhi</name></author><author><name sortKey="Uramoto, H" uniqKey="Uramoto H">H. Uramoto</name></author><author><name sortKey="Boren, J" uniqKey="Boren J">J. Borén</name></author><author><name sortKey="Cao, Y" uniqKey="Cao Y">Y. Cao</name></author><author><name sortKey="Pereira, T" uniqKey="Pereira T">T. Pereira</name></author><author><name sortKey="Akyurek, L M" uniqKey="Akyurek L">L.M. Akyürek</name></author><author><name sortKey="Poellinger, L" uniqKey="Poellinger L">L. Poellinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, A X" uniqKey="Zhou A">A.X. Zhou</name></author><author><name sortKey="Hartwig, J H" uniqKey="Hartwig J">J.H. Hartwig</name></author><author><name sortKey="Akyurek, L M" uniqKey="Akyurek L">L.M. Akyürek</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Rep</journal-id><journal-id journal-id-type="iso-abbrev">Cell Rep</journal-id><journal-title-group><journal-title>Cell Reports</journal-title></journal-title-group><issn pub-type="epub">2211-1247</issn><publisher><publisher-name>Cell Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26972007</article-id><article-id pub-id-type="pmc">4805856</article-id><article-id pub-id-type="publisher-id">S2211-1247(16)30168-1</article-id><article-id pub-id-type="doi">10.1016/j.celrep.2016.02.047</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Segura</surname><given-names>Inmaculada</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">10</xref></contrib><contrib contrib-type="author"><name><surname>Lange</surname><given-names>Christian</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">10</xref></contrib><contrib contrib-type="author"><name><surname>Knevels</surname><given-names>Ellen</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>Moskalyuk</surname><given-names>Anastasiya</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Pulizzi</surname><given-names>Rocco</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Eelen</surname><given-names>Guy</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>Chaze</surname><given-names>Thibault</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Tudor</surname><given-names>Cicerone</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Boulegue</surname><given-names>Cyril</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Holt</surname><given-names>Matthew</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Daelemans</surname><given-names>Dirk</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Matondo</surname><given-names>Mariette</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Ghesquière</surname><given-names>Bart</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Giugliano</surname><given-names>Michele</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff8" ref-type="aff">8</xref><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Ruiz de Almodovar</surname><given-names>Carmen</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn2" ref-type="fn">11</xref></contrib><contrib contrib-type="author"><name><surname>Dewerchin</surname><given-names>Mieke</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>Carmeliet</surname><given-names>Peter</given-names></name><email>peter.carmeliet@vib-kuleuven.be</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff2" ref-type="aff">2</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium</aff><aff id="aff2"><label>2</label>Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium</aff><aff id="aff3"><label>3</label>Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium</aff><aff id="aff4"><label>4</label>Proteomics Platform, Institute Pasteur, 75015 Paris, France</aff><aff id="aff5"><label>5</label>Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium</aff><aff id="aff6"><label>6</label>Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium</aff><aff id="aff7"><label>7</label>Metabolomics Core Facility, Vesalius Research Center, VIB, 3000 Leuven, Belgium</aff><aff id="aff8"><label>8</label>Neuro-Electronics Research Flanders, 3001 Leuven, Belgium</aff><aff id="aff9"><label>9</label>Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>peter.carmeliet@vib-kuleuven.be</email></corresp><fn id="fn1"><label>10</label><p id="ntpara0010">Co-first author</p></fn><fn id="fn2"><label>11</label><p id="ntpara0015">Present address: Biochemistry Center, Heidelberg University, 69120 Heidelberg, Germany</p></fn></author-notes><pub-date pub-type="pmc-release"><day>10</day><month>3</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><day>22</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>10</day><month>3</month><year>2016</year></pub-date><volume>14</volume><issue>11</issue><fpage>2653</fpage><lpage>2667</lpage><history><date date-type="received"><day>30</day><month>10</month><year>2015</year></date><date date-type="rev-recd"><day>21</day><month>12</month><year>2015</year></date><date date-type="accepted"><day>5</day><month>2</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 The Authors</copyright-statement><copyright-year>2016</copyright-year><license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</license-p></license></permissions><abstract><title>Summary</title><p>Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of <italic>Phd2</italic> induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas <italic>Flna</italic> silencing rescues the immature spine phenotype induced by PHD2 inhibition.</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>The oxygen sensor PHD2 is present in dendritic spines</p></list-item><list-item id="u0015"><label>•</label><p>PHD2 inhibition by hypoxia reduces spine maturation, synaptic density, and activity</p></list-item><list-item id="u0020"><label>•</label><p>Through hydroxylation, PHD2 targets filamin A for proteasomal degradation</p></list-item><list-item id="u0025"><label>•</label><p>Filamin A stabilization promotes dendritic spine remodeling</p></list-item></list></p></abstract><abstract abstract-type="teaser"><p>Neuronal function is highly sensitive to oxygen levels. Segura et al. show that inhibition of the oxygen sensor PHD2 induces dendritic spine regression in hippocampal neurons, thereby reducing synaptic density and network-wide neuronal activity. We identify the actin cross-linker filamin A as a target of PHD2 mediating these effects.</p></abstract></article-meta><notes><p id="misc0010">Published: March 10, 2016</p></notes></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>The Effect of Hypoxia on Dendritic Spines</p><p>(A–E) YFP-transfected MHNs were incubated for 16 hr in normoxia (A) or hypoxia (B) and analyzed for protrusion density (C), protrusion length (D), and percentage of spines with a head (E) (n = 3 experiments, 30 neurons, >800 protrusions). (A′) and (B′) show higher magnifications of the boxes in (A) and (B), respectively.</p><p>(F) Snapshot images at the start (0) and after 15, 30, 45, or 60 min of time-lapse recording of 14-DIV tdT-labeled MHNs in control (top) or hypoxia (bottom) conditions. Solid arrowheads indicate spines with a persistent increase or decrease in length. Open arrowheads indicate spines that do not change their length. Each color denotes a distinct spine. The red asterisk indicates a sprouting dendrite.</p><p>(G and H) Length of protrusions at 0 and 1 hr of recording in normoxia or hypoxia (G, n ≥ 40) and distribution of spines according to length variation (H). Stable, Δ length ≤ 0.2 μm.</p><p>Data are mean ± SEM. <sup>∗∗∗</sup>p < 0.001. Scale bars, 10 μm (A–B′) and 5 μm (F). N, normoxia; H, hypoxia (1% O<sub>2,</sub> A–E, or 0.5% O<sub>2,</sub> F–H).</p><p>Also see <xref rid="mmc1" ref-type="supplementary-material">Figures S1</xref> and <xref rid="mmc1" ref-type="supplementary-material">S2</xref>.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Synaptic Activity and Density of MHNs in Hypoxia and DMOG</p><p>(A) Spontaneous AP firing recorded from single cells by patch-clamp.</p><p>(B) Representative APs recorded by patch-clamp.</p><p>(C and D) Frequency of spontaneous AP firing (C) and network-wide AP synchronization (D) (n = 4 MEAs/condition) in MHNs in the indicated conditions.</p><p>(E–G′), vGlut (green) and PSD-95 (red) immunostaining (E′–G′) of tdT-transfected MHNs (E–G) that were subjected at 20 DIV for 16 hr to the indicated conditions. The contours of the dendrites in (E)–(G) are indicated in (E′)–(G′).</p><p>(H) Quantification of dendritic density of vGlut<sup>+</sup>/PSD-95<sup>+</sup> co-clusters (n ≥ 20 neurons) by counting the green and red co-clusters colocalizing or in immediate apposition with the dendrite/spine.</p><p>Data are mean ± SEM. <sup>∗</sup>p < 0.05 versus normoxia (A) or versus their respective 13-DIV value (C and D). <sup>∗∗∗</sup>p < 0.001. Scale bars, 10 μm. H, hypoxia (1% O<sub>2</sub>); H/N, hypoxia o/n followed by 24 hr of normoxia; D, DMOG (250 μM for A, B, G, and G′ and 1 mM for C and D); WO, washout.</p><p>Also see <xref rid="mmc1" ref-type="supplementary-material">Figure S3</xref>.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>PHD2 Expression and Silencing in Dendritic Spines</p><p>(A) Representative IB of non-PSD fraction (NS), synaptic membranes (S), and PSD-enriched fractions for the indicated proteins.</p><p>(B) Staining of MHNs for PHD2 (green) and synaptophysin (red). The bottom panels are higher magnifications (bottom left: PHD2<sup>+</sup> signal; bottom right: merged signal). Arrowheads indicate PHD2<sup>+</sup> postsynaptic clusters. Dotted lines indicate neighboring cells (high-density cultures were used to maintain neurons in culture for prolonged periods). Green/red dots outside of the soma and dendrite are stainings of neighboring cells.</p><p>(C–I) 13-DIV MHNs co-transfected with YFP plus control shRNA (scr) (C and E) or shPhd2 (D and F) were incubated for 16 hr in normoxia (C and D) or hypoxia (E and F) and analyzed for protrusion density (G), protrusion length (H), and percent of spines with a head (I) (n = 3 experiments, 21–30 neurons, 300–1,400 protrusions).</p><p>(J–K′) vGlut (green) and PSD-95 (red) immunostaining (J′ and K′) of MHNs co-transfected at 14 DIV with scr (J and J′) or shPhd2 (K and K′) together with tdT (J–L′). The contours of the dendrites in (J) and (K) are indicated in (J′) and (K′), respectively.</p><p>(L) Quantification of dendritic density of vGlut<sup>+</sup>/PSD-95<sup>+</sup> co-clusters (n ≥ 20 neurons).</p><p>(M–Q), YFP-transfected 14-DIV MHNs isolated from control (M) or PHD2<sup>NKO</sup> (N) littermates and analyzed for protrusion density (O), protrusion length (P), and number of spines with a head (Q) (n = 6 animals, >30 dendrites, >1,000 protrusions).</p><p>(R) Frequency of spontaneous network-wide AP synchronization (n = 4 MEAs/condition) of 14-DIV MHNs isolated from ctrl or PHD2<sup>NKO</sup> littermates.</p><p>(S) Representative dendritic protrusions of 14-DIV MHNs isolated from ctrl or PHD2<sup>NKO</sup> littermates upon transfection at 7 DIV with YFP (top), PHD2<sup>WT</sup>YFP (bottom left), or PHD2<sup>MUT</sup>YFP (bottom right).</p><p>(T) Analysis of dendritic protrusion density in the CA1 region of 2-week-old WT mice upon in utero electroporation at E15.5 with control shRNA (scr) or shPhd2 (n = 4–6 animals).</p><p>Data are mean ± SEM (G–I, L, and O–R) or single data plus mean ± SEM (T). <sup>∗</sup>p < 0.05, <sup>∗∗</sup>p < 0.01, <sup>∗∗∗</sup>p < 0.001. Scale bars, 10 μm (B) and 5 μm (C–F, J–K′, M, N, and S).</p><p>Also see <xref rid="mmc1" ref-type="supplementary-material">Figures S4–S6</xref>.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Filamin A Expression in Dendritic Spines</p><p>(A) SIM micrograph of YFP<sup>+</sup> (green) RHNs immunostained for endogenous FLNA (red; gray at the right). Arrowheads indicate FLNA<sup>+</sup> puncta in filopodium (top). The green dashed line indicates the contour of a dendritic spine head (bottom).</p><p>(B) 14-DIV MHNs co-transfected with tdT (red) and FLNA<sup>FL</sup>TQ2 (green) in normoxia or hypoxia.</p><p>(C) Representative IB for FLNA, VHL, and drebrin of mouse brain homogenate (H), non-synaptic fraction (NS), synaptic membranes, and PSD-enriched fractions from WT mice exposed to normoxia or hypoxia (8% O<sub>2</sub>) for 4 hr.</p><p>(D) Representative IB for FLNA and tubulin in 14-DIV MHNs subjected to normoxia or hypoxia for the indicated times.</p><p>(E) Representative IB for FLNA and tubulin in 14-DIV untreated MHNs or MHNs treated with DMOG for 2 hr.</p><p>(F) Representative IB for FLNA and tubulin in untreated MHNs (−) or treated with DMOG (D), MG132 (MG), actinomycin D (Ac), or cycloheximide (Cy) in normoxia or hypoxia.</p><p>(G) Representative IB for FLNA and tubulin in MHNs treated for 2 hr with increasing concentrations of MG132.</p><p>(H) IB for FLNA, PHD2, myc, and tubulin in MHNs transduced with scrambled control shRNA, shPhd2, or overexpressing mycFLNA<sup>D21–D23-WT</sup>.</p><p>(I) Representative IB for the indicated proteins of mouse brain homogenate (H), non-synaptic fraction, synaptic membranes, and PSD-enriched fractions obtained from ctrl or PHD2<sup>NKO</sup> littermates.</p><p>Synaptop., synaptophysin. Densitometry of IBs as shown in (C)–(I) is shown in <xref rid="mmc1" ref-type="supplementary-material">Figure S7</xref>. Scale bars, 1 μm (A) and 10 μm (B).</p><p>Also see <xref rid="mmc1" ref-type="supplementary-material">Figure S7</xref>.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Analysis of Filamin A as a PHD2 Target</p><p>(A) Representative IB for YFP and myc after IP of mycFLNA<sup>FL</sup> from HEK293T cells co-expressing mycFLNA<sup>FL</sup> and PHD2<sup>WT</sup>YFP or PHD2<sup>MUT</sup>YFP. Total lysates are shown below.</p><p>(B) Representative IB for FLNA and PHD2 after IP of PHD2 in mouse brain homogenate, non-synaptic fraction, synaptic membranes, and PSD fractions. Total lysates are shown below.</p><p>(C) Top: diagrams of the domains of full-length (FL) and deletion constructs of FLNA. 1–24, IgG repeats; H1 and H2, hinges. Bottom: representative IB for myc and YFP after IP of myc-tagged FLNA deletion mutants co-expressed with PHD2<sup>MUT</sup>YFP in HEK293T cells. Arrows indicate myc-tagged proteins and PHD2<sup>MUT</sup>YFP. Asterisks indicate aspecific bands.</p><p>(D) Representative fluorescence lifetime images (FLIM) and life time measurements of FLNA<sup>CT</sup>TQ2 when transfected alone or in combination with YFP, PHD2<sup>WT</sup>YFP, or PHD2<sup>MUT</sup>YFP in HEK293T cells (mean ± SEM, n ≥ 50 cells).</p><p>(E) Representative IB for hydroxyprolines (OH-Pro) or myc after IP of mycFLNA<sup>FL</sup> from HEK293T cells transfected with mycFLNA<sup>FL</sup> and treated for 2 hr with MG132 or lactacystin (L). Total lysates are shown below.</p><p>(F) Representative IB and densitometric quantification for FLNA and OH-Pro after IP with control IgG (left) or specific antibodies for FLNA (right) of brain homogenates from P10 rats housed in ctrl or hypoxia chambers.</p><p>(G) MS/MS fragmentation spectra of unmodified (a, from control HEK293T cells) and hydroxylated (b, from PHD2<sup>WT</sup>YFP-transfected HEK293T cells treated with MG132 for 2 hr) P2316 in FNEEHIPDSPFVVPVASPSGDAR of FLNA, focusing on the fragment ion (y10), showing a mass shift of 16 Da upon hydroxylation. Complete spectra are shown in <xref rid="mmc1" ref-type="supplementary-material">Figure S8</xref>G.</p><p>(H) Representative IB for the indicated proteins after IP of myc in HEK293T cells co-transfected with PHD2<sup>WT</sup>YFP together with mycFLNA<sup>D21–D23-WT</sup>, mycFLNA<sup>D21–D23-P2309A</sup>, or mycFLNA<sup>D21–D23-P2316A</sup> and subjected to ctrl (left) or DMOG (right) treatment. Total lysates are shown below.</p><p>Also see <xref rid="mmc1" ref-type="supplementary-material">Figure S8</xref>.</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>Analysis of Filamin A Interaction with VHL</p><p>(A) Representative IB for myc and HA after IP of myc from HEK293T cells transfected with mycFLNA<sup>FL</sup> and HA-VHL. Total lysates are shown below.</p><p>(B) Representative IB for myc and HA after IP of myc from HEK293T cells transfected with mycFLNA<sup>CT</sup>, mycFLNA<sup>D21–D23-WT</sup>, or mycFLNA<sup>H2-D24</sup> together with HA-VHL (left). Total lysates are shown (right). Arrowheads indicate myc-tagged proteins. Asterisks indicate IgGs used for the IP.</p><p>(C) Representative IB for myc and HA after IP of myc from HEK293T cells transfected with HA-VHL alone or co-transfected with mycFLNA<sup>D21–D23-WT</sup>, mycFLNA<sup>D21–D23-P2309A</sup>, mycFLNA<sup>D21–D23-P2316A</sup>, or mycFLNA<sup>D21–D23-3P→A</sup> mutants. Total lysates are shown below.</p><p>(D) Representative IB for FLNA and tubulin in MHNs transduced with a control shRNA (scr) or shVhl (left). Also shown is densitometric quantification of FLNA protein levels (right, mean ± SEM, n = 3, <sup>∗</sup>p < 0.05).</p><p>(E and F) Representative IBs for FLNA, HIF-1α, and tubulin (E) or for FLNA, hydroxyprolines (OH-Pro), and tubulin (F) of brain homogenates from E14.5 ctrl or VHL<sup>NKO</sup> littermates.</p><p>(G) Representative IB for FLNA and tubulin after TUBE2 pull-down of brain homogenates obtained from E14.5 ctrl or VHL<sup>NKO</sup> littermates. Total lysates are shown below.</p><p>Also see <xref rid="mmc1" ref-type="supplementary-material">Figure S9</xref>.</p></caption><graphic xlink:href="gr6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>The Effect of Filamin A Upregulation on Spine Maturation</p><p>(A) Representative IB for FLNA, myc, and actin in HEK293T cells under control or hypoxia (0.2% O<sub>2</sub>) conditions or after transfection with mycFLNA<sup>D21–D23-WT</sup> (left). Also shown is densitometric quantification of FLNA (right).</p><p>(B) Representative IB for myc and YFP after IP of myc in the presence of recombinant GST or GST-FLNA<sup>D21–D23</sup> proteins from homogenates of HEK293T cells co-transfected with mycFLNA<sup>FL</sup> and PHD2<sup>WT</sup>YFP. Left (input): total lysate control in co-transfected HEK293T cells. Densitometric quantification of the PHD2<sup>WT</sup>YFP/mycFLNA<sup>FL</sup> ratio is shown (n = 3, <sup>∗</sup>p < 0.05).</p><p>(C–H), Representative images of tdT<sup>+</sup> 14-DIV ctrl (C), mycFLNA<sup>D21–D23-WT</sup> (D), or mycFLNA<sup>D21–D23-3P→A</sup> (E) transfected MHNs. Also shown is quantification of protrusion density (F), protrusion length (G), and percentage of spines with a head (H) (n = 10 neurons, 324–731 protrusions).</p><p>(I–K′) Immunostaining of vGlut (green) and PSD-95 (red) (I′, J′, and K′) in 21-DIV tdT-transfected MHN (I–K) alone (I and I′) or together with mycFLNA<sup>D21–D23-WT</sup> (J and J′) or mycFLNA<sup>D21–D23-3P→A</sup> (K and K′). The contours of the dendrites in (I), (J), and (K) are indicated in (I′), (J′), and (K′), respectively.</p><p>(L) Quantification of the dendritic density of vGlut<sup>+</sup>/PSD-95<sup>+</sup> co-clusters (n ≥ 20 neurons).</p><p>(M–P) Representative images of 14-DIV MHNs co-transfected with tdT together with scrambled control shRNA (M), shPhd2 (N), shFlna (O), or both shPhd2 and shFlna (P).</p><p>(Q–S) Quantification of protrusion density (Q), protrusion length (R), and percentage of spines with a head (S) (n ≥ 7 neurons, 7–22 dendrites, 170–832 protrusions).</p><p>Data are mean ± SEM. <sup>∗</sup>p < 0.05, <sup>∗∗∗</sup>p < 0.001 versus ctrl or scr. #p < 0.05, ##p < 0.01, ###p < 0.001 versus shPhd2 or mycFLNA<sup>D21–D23-WT</sup>. Scale bars, 5 μm.</p></caption><graphic xlink:href="gr7"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Belgique</li><li>France</li><li>Suisse</li></country><region><li>Canton de Vaud</li><li>Province d'Anvers</li><li>Province du Brabant flamand</li><li>Île-de-France</li></region><settlement><li>Anvers</li><li>Heverlee</li><li>Lausanne</li><li>Louvain</li><li>Paris</li></settlement><orgName><li>Université d'Anvers</li></orgName></list><tree><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Segura, Inmaculada" sort="Segura, Inmaculada" uniqKey="Segura I" first="Inmaculada" last="Segura">Inmaculada Segura</name></region><name sortKey="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><name sortKey="Carmeliet, Peter" sort="Carmeliet, Peter" uniqKey="Carmeliet P" first="Peter" last="Carmeliet">Peter Carmeliet</name><name sortKey="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name><name sortKey="Dewerchin, Mieke" sort="Dewerchin, Mieke" uniqKey="Dewerchin M" first="Mieke" last="Dewerchin">Mieke Dewerchin</name><name sortKey="Dewerchin, Mieke" sort="Dewerchin, Mieke" uniqKey="Dewerchin M" first="Mieke" last="Dewerchin">Mieke Dewerchin</name><name sortKey="Eelen, Guy" sort="Eelen, Guy" uniqKey="Eelen G" first="Guy" last="Eelen">Guy Eelen</name><name sortKey="Eelen, Guy" sort="Eelen, Guy" uniqKey="Eelen G" first="Guy" last="Eelen">Guy Eelen</name><name sortKey="Ghesquiere, Bart" sort="Ghesquiere, Bart" uniqKey="Ghesquiere B" first="Bart" last="Ghesquière">Bart Ghesquière</name><name sortKey="Giugliano, Michele" sort="Giugliano, Michele" uniqKey="Giugliano M" first="Michele" last="Giugliano">Michele Giugliano</name><name sortKey="Giugliano, Michele" sort="Giugliano, Michele" uniqKey="Giugliano M" first="Michele" last="Giugliano">Michele Giugliano</name><name sortKey="Holt, Matthew" sort="Holt, Matthew" uniqKey="Holt M" first="Matthew" last="Holt">Matthew Holt</name><name sortKey="Knevels, Ellen" sort="Knevels, Ellen" uniqKey="Knevels E" first="Ellen" last="Knevels">Ellen Knevels</name><name sortKey="Knevels, Ellen" sort="Knevels, Ellen" uniqKey="Knevels E" first="Ellen" last="Knevels">Ellen Knevels</name><name sortKey="Lange, Christian" sort="Lange, Christian" uniqKey="Lange C" first="Christian" last="Lange">Christian Lange</name><name sortKey="Lange, Christian" sort="Lange, Christian" uniqKey="Lange C" first="Christian" last="Lange">Christian Lange</name><name sortKey="Moskalyuk, Anastasiya" sort="Moskalyuk, Anastasiya" uniqKey="Moskalyuk A" first="Anastasiya" last="Moskalyuk">Anastasiya Moskalyuk</name><name sortKey="Pulizzi, Rocco" sort="Pulizzi, Rocco" uniqKey="Pulizzi R" first="Rocco" last="Pulizzi">Rocco Pulizzi</name><name sortKey="Ruiz De Almodovar, Carmen" sort="Ruiz De Almodovar, Carmen" uniqKey="Ruiz De Almodovar C" first="Carmen" last="Ruiz De Almodovar">Carmen Ruiz De Almodovar</name><name sortKey="Ruiz De Almodovar, Carmen" sort="Ruiz De Almodovar, Carmen" uniqKey="Ruiz De Almodovar C" first="Carmen" last="Ruiz De Almodovar">Carmen Ruiz De Almodovar</name><name sortKey="Segura, Inmaculada" sort="Segura, Inmaculada" uniqKey="Segura I" first="Inmaculada" last="Segura">Inmaculada Segura</name><name sortKey="Tudor, Cicerone" sort="Tudor, Cicerone" uniqKey="Tudor C" first="Cicerone" last="Tudor">Cicerone Tudor</name></country><country name="France"><region name="Île-de-France"><name sortKey="Chaze, Thibault" sort="Chaze, Thibault" uniqKey="Chaze T" first="Thibault" last="Chaze">Thibault Chaze</name></region><name sortKey="Boulegue, Cyril" sort="Boulegue, Cyril" uniqKey="Boulegue C" first="Cyril" last="Boulegue">Cyril Boulegue</name><name sortKey="Matondo, Mariette" sort="Matondo, Mariette" uniqKey="Matondo M" first="Mariette" last="Matondo">Mariette Matondo</name></country><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Giugliano, Michele" sort="Giugliano, Michele" uniqKey="Giugliano M" first="Michele" last="Giugliano">Michele Giugliano</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Belgique/explor/OpenAccessBelV2/Data/Pmc/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000006 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd -nk 000006 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Belgique
|area= OpenAccessBelV2
|flux= Pmc
|étape= Checkpoint
|type= RBID
|clé= PMC:4805856
|texte= The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/RBID.i -Sk "pubmed:26972007" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a OpenAccessBelV2
| This area was generated with Dilib version V0.6.25. |  |