Annotated protein:Dixin (Coiled-coil protein DIX1) (Coiled-coil-DIX1) (DIX domain-containing protein 1). Gene symbol: DIXDC1. Taxonomy: Mus musculus (Mouse). Uniprot ID: Q80Y83
antibody wiki:
SynGO gene info:SynGO data @ DIXDC1
Ontology domain:Biological Process
SynGO term:modification of postsynaptic actin cytoskeleton (GO:0098885)
Synapse type(s):cerebral cortex, glutamatergic
hippocampus, glutamatergic
Annotated paper:Kwan V, et al. "DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants" Cell Rep. 2016 Nov 8;17(7):1892-1904 PMID:27829159
Figure(s):Figure 4, 5
Annotation description:Figure 4, S4B: Phosphorylation of DIXDC1 isoforms by MARK1 regulates neuronal morphology.
"We also examined whether phosphorylation of DIXDC1 was important for its localization in dendrites and spines. Cultured cortical neurons showed co-localization of GFP-tagged hDIXDC1-WT (isoforms 1 and 2) with PSD95 in the dendritic spines (Figures 4G and 4H). However, the hDIXDC1-S592A and -S381A phospho-mutants both exhibited a decrease in PSD95 co-localization, indicating DIXDC1 localization to spines was disrupted (Figures 4G and 4H). These results strongly indicate that phosphorylation of both DIXDC1 isoforms is critical for cortical dendrite and synapse formation."

Figure 5: Phosphorylation of DIXDC1 regulates cytoskeleton dynamics and spine growth.

"We next explored whether phosphorylation of DIXDC1 regulates the actin cytoskeleton. We monitored actin dynamics in DIV2-3 hippocampal neurons due to the reliability for live imaging at this age and used Lifeact-GFP to monitor actin (Riedl et al., 2008, Riedl et al., 2010; Figures 5F and S6E; Movies S1, S2, S3, S4, and S5).

Interestingly, we found that WT-DIXDC1 isoform 1, but not isoform 2, significantly alters F-actin retrograde speed (Figures 5F and 5G). Furthermore, both the hDIXDC1-S592A (isoform 1) and -S381A (isoform 2) mutants were different than their WT counterparts with respect to their impact on retrograde speed, suggesting the isoforms differentially regulate actin (Figures 5F and 5G).

We also found the percentage of neurites with an intact growth cone was reduced in neurons expressing hDIXDC1-S592A (isoform 1) or hDIXDC1-S381A (isoform 2), indicating that MARK1 phosphorylation is required for actin integrity (Figure 5I).

JPK treatment was found to increase spine density and reduce the number of thin spines in neurons expressing hDIXDC1-S592A isoform 1 or hDIXDC1-S381A isoform 2 to levels comparable to JPK-treated WT neurons (Figures S6C and S6D). This demonstrates that enhancing actin polymerization improves spine deficits caused by the phosphorylation mutations."

authors conclude:
"We discovered that MARK1, previously linked to ASDs, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner."
Evidence tracking, Biological System:Cultured neurons
Evidence tracking, Protein Targeting:Genetic transformation (eg; knockout, knockin, mutations)
Over-expression
RNAi / shRNA
Evidence tracking, Experiment Assay:Confocal
Annotator(s):Frank Koopmans (ORCID:0000-0002-4973-5732)
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
Additional literature:"Both visual inspection and Sholl analysis revealed no significant differences in dendrite arborization in neurons from Dixdc1KO neonates in the mixed outbred genetic background (Supplementary Figures 3a-c); however, mutant neurons had significantly reduced spine density along primary dendrites (Figures 1e and f) and a significantly increased percentage of immature (filopodial) spines (Figures 1e and g)." @ PMID:27752079
SynGO annotation ID:5216
Dataset release (version):20231201
View annotation as GO-CAM model:Gene Ontology