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Cell Rep. 2016 Mar 22;14(11):2653-67. doi: 10.1016/j.celrep.2016.02.047. Epub 2016 Mar 10.

The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A.

Author information

1
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.
2
Laboratory of Theoretical Neurobiology and Neuroengineering, University of Antwerp, 2610 Wilrijk, Belgium.
3
Proteomics Platform, Institute Pasteur, 75015 Paris, France.
4
Laboratory of Glia Biology, VIB, 3000 Leuven, Belgium.
5
Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
6
Metabolomics Core Facility, Vesalius Research Center, VIB, 3000 Leuven, Belgium.
7
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.
8
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.

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.

PMID:
26972007
PMCID:
PMC4805856
DOI:
10.1016/j.celrep.2016.02.047
[Indexed for MEDLINE]
Free PMC Article

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