title: The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A.
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 Phd2 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 Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition.
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Segura
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Lange
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Knevels
authors.affiliation: Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Moskalyuk
authors.affiliation: Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium.
authors.forename: Rocco
authors.initials: R
authors.lastname: Pulizzi
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Proteomics Platform, Institute Pasteur, 75015 Paris, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Chaze
authors.affiliation: Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium.
authors.forename: Cicerone
authors.initials: C
authors.lastname: Tudor
authors.affiliation: Proteomics Platform, Institute Pasteur, 75015 Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Boulegue
authors.affiliation: Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium.
authors.forename: Matthew
authors.initials: M
authors.lastname: Holt
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.affiliation: Proteomics Platform, Institute Pasteur, 75015 Paris, France.
authors.forename: Mariette
authors.initials: M
authors.lastname: Matondo
authors.affiliation: Metabolomics Core Facility, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium; Neuro-Electronics Research Flanders, 3001 Leuven, Belgium; Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Giugliano
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz de Almodovar
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium. Electronic address: peter.carmeliet@vib-kuleuven.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism*; D064448:Filamins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D064448:Filamins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014404:Tubulin; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse; D010100:Oxygen; C040947:oxalylglycine