| Annotated protein: | von Hippel-Lindau disease tumor suppressor (pVHL). Gene symbol: VHL. Taxonomy: Mus musculus (Mouse). Uniprot ID: P40338 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ VHL |
| Ontology domain: | Biological Process |
| SynGO term: | regulation protein catabolic process at postsynapse (GO:0140252) |
| Synapse type(s): | hippocampus, glutamatergic |
| Annotated paper: | Segura I, et al. "The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A" Cell Rep. 2016 Mar 22;14(11):2653-67 PMID:26972007 |
| Figure(s): | Fig.3, 5, 6, 7, Suppl.Fig.9 |
| Annotation description: | Complicated story: Egl nine homolog 1; PHD2 is a oxygen sensor that is known to hydroxylate proline residues in target proteins. The E3 ubiquitin ligase von Hippel-Lindau (VHL) is known to ubiquitinate these hydroxylated proteins triggering proteasomal degradation. This paper shows that Egl nine homolog 1; PHD2 is involved in the remodelling of dendritic spines. This remodeling involves proline-hydroxylation of Filamin and its degradation via VHL. Fig.3: "Phd2 Silencing Impairs Dendritic Spine Maturation" - "At 14 DIV, Phd2 silencing reduced dendritic protrusion density and the frequency of spines with a head, whereas it increased protrusion length (Figures 3C, 3D, and 3G-3I). Hypoxia did not further alter these parameters in Phd2-silenced MHNs (Figures 3E-3I)...Phd2 silencing also impaired synaptic density, as revealed by the reduced number of vGlut1+/PSD-95+ co-clusters (Figures 3J-3L) and synaptophysin+ clusters (Figures S4M-S4Q)." Fig.3: "Loss of PHD2 Impairs Dendritic Spine Maturation" - "Compared with control RFP+ neurons, YFP+ or CFP+ PHD2-deficient cells had reduced protrusion density and increased protrusion length (Figure S4U). Similar results were obtained in MNHs from mice lacking PHD2 in neurons (PHD2NKO) (Figures 3M-3Q; Figure S4V). " - "Thus, PHD2-mediated hydroxylation is required to induce dendritic spine maturation." Fig.3: "Phd2 Regulates Dendritic Spine and Synaptic Density In Vivo" - "Analysis of dendritic spines in the hippocampal CA1 region on postnatal day 15 (P15) revealed that spine density was reduced in shPhd2 neurons in vivo (Figure 3T; Figures S6A and S6B)." Fig.4: - "FLNA Is Expressed in Dendritic Filopodia and Spines" - "FLNA Is Stabilized by Hypoxia, DMOG, or PHD2 Knockdown" Fig.5: - "PHD2 Interacts with Domains D21-D23 of FLNA" - "PHD2 Hydroxylates Proline Residues P2309 and P2316 in FLNA" Fig.6: - "VHL Regulates FLNA Protein Levels" - "Taken together, our results suggest that hydroxylation of P2309, P2316, and possibly P2312 was required for the interaction of FLNA with VHL." - "VHL Ubiquitinates FLNA" Fig.7: - "FLNA Levels Determine Dendritic Spine Morphology" - "We explored whether Flna silencing reverted the phenotype induced by silencing Phd2. We co-transfected MHNs with tdT together with scr or Flna-specific shRNA (shFlna) alone or together with shPhd2. shFlna reduced FLNA protein levels by 59% ± 8% (n = 3, p < 0.05). Silencing of Flna in MHNs alone increased protrusion length without affecting the protrusion density or the number of spines with a head (Figures 7M-7S). However, in Phd2-silenced MHNs, Flna silencing largely prevented the switch to a more immature spine phenotype (Figures 7M-7S). Thus, FLNA is required for the spine morphology changes induced by PHD2 knockdown." Suppl.Fig.9: "Notably, 14-DIV MHNs of E15.5 VHLNKO mice (containing higher levels of endogenous FLNA) also showed more immature dendritic spines (Figures S9G and S9H). |
| Evidence tracking, Biological System: | Intact tissue Cultured neurons Non-neuronal tissue |
| Evidence tracking, Protein Targeting: | Genetic transformation (eg; knockout, knockin, mutations) RNAi / shRNA Over-expression |
| Evidence tracking, Experiment Assay: | Confocal Western blot Biochemical fractionation (generic) |
| Annotator(s): | Pim van Nierop (ORCID:0000-0003-0593-3443) Guus Smit (ORCID:0000-0002-2286-1587) Matthijs Verhage (ORCID:0000-0002-2514-0216) |
| Lab: | Department of Functional Genomics, Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands |
| SynGO annotation ID: | 2670 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |