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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cells, Cultured
  • Dendritic Spines / metabolism*
  • Filamins / antagonists & inhibitors
  • Filamins / genetics
  • Filamins / metabolism*
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • Mice
  • Mice, Knockout
  • Oxygen / metabolism
  • Rats
  • Rats, Wistar
  • Synapses / metabolism*
  • Tubulin / metabolism
  • Up-Regulation / drug effects
  • Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Amino Acids, Dicarboxylic
  • Filamins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Tubulin
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse
  • Oxygen
  • oxalylglycine