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.

The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A / Segura, I.; Lange, C.; Knevels, E.; Moskalyuk, A.; Pulizzi, R.; Eelen, G.; Chaze, T.; Tudor, C.; Boulegue, C.; Holt, M.; Daelemans, D.; Matondo, M.; Ghesquiere, B.; Giugliano, M.; Ruiz de Almodovar, C.; Dewerchin, M.; Carmeliet, P.. - In: CELL REPORTS. - ISSN 2211-1247. - 14:11(2016), pp. 2653-2667. [10.1016/j.celrep.2016.02.047]

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

Giugliano, M.;
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 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.
2016
14
11
2653
2667
The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A / Segura, I.; Lange, C.; Knevels, E.; Moskalyuk, A.; Pulizzi, R.; Eelen, G.; Chaze, T.; Tudor, C.; Boulegue, C.; Holt, M.; Daelemans, D.; Matondo, M.; Ghesquiere, B.; Giugliano, M.; Ruiz de Almodovar, C.; Dewerchin, M.; Carmeliet, P.. - In: CELL REPORTS. - ISSN 2211-1247. - 14:11(2016), pp. 2653-2667. [10.1016/j.celrep.2016.02.047]
Segura, I.; Lange, C.; Knevels, E.; Moskalyuk, A.; Pulizzi, R.; Eelen, G.; Chaze, T.; Tudor, C.; Boulegue, C.; Holt, M.; Daelemans, D.; Matondo, M.; Ghesquiere, B.; Giugliano, M.; Ruiz de Almodovar, C.; Dewerchin, M.; Carmeliet, P.
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S2211124716301681-main.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 6.21 MB
Formato Adobe PDF
6.21 MB Adobe PDF Visualizza/Apri
mmc1.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 4.49 MB
Formato Adobe PDF
4.49 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1333753
Citazioni
  • ???jsp.display-item.citation.pmc??? 29
  • Scopus 43
  • ???jsp.display-item.citation.isi??? 43
social impact