Contributors: Laboratory of Angiogenesis and Vascular Metabolism Leuven, Belgium (VIB-CCB); Department of Oncology Leuven, Belgium; Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven)-Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven); VIB Vesalius Research Center (VRC); Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven); Universiteit Antwerpen = University of Antwerpen Antwerpen; Plateforme de Protéomique / Proteomics platform; Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio); Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS); Laboratory of Glia Biology Leuven, Belgium; Leuven Center for Cancer Biology (VIB-KU-CCB); Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie Ghent, Belgique (VIB)-Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie Ghent, Belgique (VIB); Rega Institute for Medical Research Leuven, België; Neuroelectronics Research Flanders (NERF); Brain Mind Institute (BMI - EPFL); Ecole Polytechnique Fédérale de Lausanne (EPFL); I.S. was supported by the Marie Curie FP7 program. I.S. and C.L. are postdoctoral fellows of the Research Foundation Flanders (FWO). C.T. was supported by European Research Council Starting Grant 281961–ASTROFUNC (to M.H.). This work was supported by Belgian Science Policy Grants IAP-P6/20 (to M.D.) and IAP-P7/20 (to M.D. and M.G.); EC-FP7 Grants 264872–NAMASEN, 306502–BRAINLEAP, and 286403–NEUROACT (to M.G.), FWO Grants G.0671.12N (to P.C.), 1.5.244.11N (to I.S.), and G088812N (to M.G.); and long-term structural Methusalem funding by the Flemish government and the Foundation Leducq Transatlantic Network (ARTEMIS) (to P.C.).; We thank M.S. Ramer, L. Moons, R. Klein, and P. Maxwell for scientific discussion and critical reading of the manuscript. We thank R. Klein (Martinsreid) for the NestinCre mice, J. Blenis (Harvard) for pcDNA3-myc-hFLNA-WT, J. Goedhart (Amsterdam) for Turquoise2 plasmids, J. Livet (Paris) for the Brainbow1.0 plasmid, W. Kaelin (Harvard) for the HA-VHL plasmid, and J. de Wit (Leuven) for the vGlut1 antibody. We acknowledge L. Notebaert, M. Wijnants, D. van Dick, technical staff, and Vesalius Research Center core facilities.; European Project: 281961,EC:FP7:ERC,ERC-2011-StG_20101109,ASTROFUNC(2012); European Project: 264872,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,NAMASEN(2011); European Project: 306502,EC:FP7:ICT,FP7-ICT-2011-C,BRAINLEAP(2013); European Project: 286403,EC:FP7:PEOPLE,FP7-PEOPLE-2011-IAPP,NEUROACT(2012)
نبذة مختصرة : International audience ; 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.
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