Disease relevance of Dcx

• Mutational and expression analysis of the reelin pathway components CDK5 and doublecortin in gangliogliomas [1].
• Doublecortin (DCX) is one of the three genes found from Affymetrix gene chip analysis related to glioma patient survival [2].
• Ectopic doublecortin gene expression suppresses the malignant phenotype in glioblastoma cells [2].
• To determine how neuronal NO synthase affects ischemia-induced neurogenesis, transient focal cerebral ischemia was produced in wild-type mice and in knockout mice lacking neuronal NO synthase, and BrdU incorporation and doublecortin immunoreactivity were measured in the principal neuroproliferative regions of the adult brain [3].
• Doublecortin is preferentially expressed in invasive human brain tumors [4].

High impact information on Dcx

• Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain [5].
• A second locus, doublecortin-like kinase (Dclk), encodes a protein with similar "doublecortin domains" and microtubule stabilization properties that may compensate for Dcx [6].
• Dcx and Dclk may directly or indirectly regulate microtubule-based vesicle transport, a process critical to both neuronal migration and axon outgrowth [6].
• Dcx/Dclk-deficient dissociated neurons show abnormal axon outgrowth and dendritic structure, with defects in axonal transport of synaptic vesicle proteins [6].
• Doublecortin-like kinase controls neurogenesis by regulating mitotic spindles and M phase progression [7].

Chemical compound and disease context of Dcx

• Ectopic expression of doublecortin protects adult rat progenitor cells and human glioma cells from severe oxygen and glucose deprivation [8].

Biological context of Dcx

• Mass spectrometry and Western blot analysis indicate phosphorylation at Dcx residue Ser297 [9].
• Using a yeast two-hybrid screen with Dcx as bait, we have isolated neurabin II/spinophilin, an F-actin binding protein known to play a role in dendritic spine formation [10].
• Because dynamic cellular asymmetries such as those seen in cell migration critically depend on a cooperation between the microtubule and actin cytoskeletal filament systems, we investigated whether Dcx, a microtubule-associated protein, is engaged in cytoskeletal cross-talk [11].
• Mutagenesis and pull-down experiments showed that these interactions were mediated through a tyrosine-based sorting signal (YLPL) in the C-terminal part of Doublecortin [12].
• Taken together these data indicate that a certain proportion of Doublecortin interacts with AP-1 and/or AP-2 in vivo and are consistent with a potential involvement of Doublecortin in protein sorting or vesicular trafficking [12].

Anatomical context of Dcx

• Phosphorylation of Dcx lowers its affinity to microtubules in vitro, reduces its effect on polymerization, and displaces it from microtubules in cultured neurons [9].
• Although the phosphomimetic green fluorescent protein (GFP)-Dcx(S47E) transfected into COS-7 cells had a reduced affinity for microtubules, we found that pseudophosphorylation was not sufficient to cause Dcx to bind to F-actin [11].
• Doublecortin association with actin filaments is regulated by neurabin II [11].
• We studied doublecortin-like kinase expression in mouse using Northern blot analysis, in situ hybridization, and Western blot analysis, and conclude that doublecortin-like kinase is expressed in multiple regions of embryonic brain including the developing cerebral cortex [13].
• While analyzing active genes in neonatal mouse hippocampus by quantitative 3'-cDNA collection, we identified a highly conserved murine homolog of doublecortin, the causative gene of X-linked lissencephaly (XLIS) and subcortical laminar heterotopia (SCLH) syndrome [14].

Associations of Dcx with chemical compounds

• Early after BrdU, CR colocalized with immature neuronal marker doublecortin; and later with persisting neuronal marker NeuN [15].
• Ipsilateral GCD progressively developed after KA injection and was paralleled by a gradual decrease in the expression of doublecortin, a marker of newly generated granule cells, in the dentate subgranular layer [16].
• In vitro assays (using biochemical methods, DIC microscopy and electron microscopy) demonstrate that Doublecortin binds microtubules directly, stabilizes them and causes bundling [17].
• Therefore, SGZ progenitor cells committed to a neuronal phenotype before KA treatment complete their differentiation despite the rapid down-regulation of doublecortin and PSA-NCAM [18].
• In addition, blocking endothelial nitric oxide synthase activity (via a daily injection of 20 mg/kg L-nitroimidazole ornithine) during exercise reduced the number of cells within the dentate gyrus that were immunoreactive for Ki-67 protein and doublecortin [19].

Regulatory relationships of Dcx

• The isolated kinase domain retains catalytic activity and is structurally similar to CPG16, a second product of the DCLK gene expressed in the adult brain that lacks the doublecortin domain [20].

Other interactions of Dcx

• Multisite phosphorylation of doublecortin by cyclin-dependent kinase 5 [21].
• DCLK consists of an N-terminal doublecortin domain, responsible for its localization to microtubules, and a C-terminal serine-threonine kinase domain [20].
• NeuroD and doublecortin, markers normally distinguishing the discrete layered organization of granule cell maturation in the inner EGL, are aberrantly expressed in the outer EGL where MATH1-positive, proliferating cells reside [22].
• Recently, we and others reported that the doublecortin gene is responsible for X-linked lissencephaly and subcortical laminar heterotopia [23].
• Cleavage of doublecortin-like kinase by calpain releases an active kinase fragment from a microtubule anchorage domain [20].

Analytical, diagnostic and therapeutic context of Dcx

• Immunoprecipitation experiments with brain extracts show that neurabin II and Dcx interact in vivo [10].
• We now demonstrate that Dcx co-sediments with actin filaments (F-actin), and using light and electron microscopy and spin down assays, we show that Dcx induces bundling and cross-linking of microtubules and F-actin in vitro [11].
• In utero RNA interference (RNAi) of Dcx in rats, in contrast, creates an animal model of SBH [24].
• MRI and cryosectioning showed agenesis of the corpus callosum in Dcx knockout mice on this background and an intermediate, partial agenesis in heterozygote mice [25].
• We report that intranasal administration of either fibroblast growth factor-2 or heparin-binding epidermal growth factor-like growth factor increases neurogenesis, measured by the incorporation of bromodeoxyuridine into cells that express the early neuronal marker protein doublecortin in the subventricular zone of mouse brain [26].

References