Disease relevance of Dvl1

• Finally, 2-3% of Dvl2(-/-) embryos displayed thoracic spina bifida, while virtually all Dvl1/2 double mutant embryos displayed craniorachishisis, a completely open neural tube from the midbrain to the tail [1].
• Treatment with pertussis toxin or knock down of Galpha(q) or Galpha(o) blocks Wnt stimulation of casein kinase 2 activation, as does suppression of the phosphoprotein Dishevelled, demonstrating that casein kinase 2 is downstream of heterotrimeric G proteins and Dishevelled [2].
• Using mouse neuroblastoma 2A (N2A) cells as a model system, we have found that overexpression of Dvl promotes the outgrowth of neurite-like processes, and leads to the induction of a striking, bipolar morphologic phenotype during neuronal differentiation [3].
• Human homologue sequences to the Drosophila dishevelled segment-polarity gene are deleted in the DiGeorge syndrome [4].
• cDNA cloning of a human dishevelled DVL-3 gene, mapping to 3q27, and expression in human breast and colon carcinomas [5].

Psychiatry related information on Dvl1

• We reported previously that mice deficient in Dvl1 exhibited abnormal social interaction and sensorimotor gating [6].

High impact information on Dvl1

• Here, we report that the bicoid-related transcription factor Pitx2 is rapidly induced by the Wnt/Dvl/beta-catenin pathway and is required for effective cell-type-specific proliferation by directly activating specific growth-regulating genes [7].
• Moreover, Dvl contributes to cytoskeletal reorganization during gastrulation and mitotic spindle orientation during asymmetric cell division [8].
• Differences in the binding affinity of the Dvl PDZ domain and its binding partners may be important in regulating signal transduction by Dvl [9].
• By using NMR spectroscopy, we determined that an internal sequence of Fz binds to the conventional peptide binding site in the PDZ domain of Dvl; this type of site typically binds to C-terminal binding motifs [9].
• These findings demonstrate a new function for the non-canonical Wnt pathway in dendrite development and identify Dvl as a regulator of Rho GTPases and JNK during dendritic morphogenesis [10].

Biological context of Dvl1

• Thus, Dvl2 is essential for normal cardiac morphogenesis, somite segmentation and neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in some phenotypes [1].
• The predicted amino acid sequence shares 64 and 62% identity to Dvl1 and Dvl2, respectively [11].
• Dvl2 and Dvl3 genomic clones were isolated from a mouse 129 strain gamma FIXII genomic library and have identical exon/intron organization to Dvl1 [12].
• We find that phosphorylation of Dvl strongly enhances its interaction with betaarr1, suggesting that regulation of Dvl phosphorylation and subsequent interaction with betaarr1 may play a key role in the activation of the LEF transcription pathway [13].
• Dishevelled proteins regulate cell adhesion in mouse blastocyst and serve to monitor changes in Wnt signaling [14].

Anatomical context of Dvl1

• Expression of dominant-negative Dvl1 in postsynaptic muscle cells reduces the amplitude of spontaneous synaptic currents at the NMJ [15].
• This suggests that perturbing Dvl function interferes with cell-cell adhesion through the non-canonical Wnt pathway in blastocysts [14].
• Here we show that three of the mouse Dishevelled proteins are not only expressed in oocytes and during preimplantation development, but also display distinct spatio-temporal localization [14].
• Stage-dependent Dishevelled-1 expression during mouse spermatogenesis suggests a role in regulating spermatid morphological changes [16].
• More importantly, axonal microtubules are stabilized after DVL localizes to axons [17].

Associations of Dvl1 with chemical compounds

• Redox-dependent activation of the Wnt-beta-catenin pathway occurs independently of extracellular Wnts and is impaired by RNAi of NRX . In addition, association between Dvl and NRX is inhibited by H(2)O(2) treatment [18].
• Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3beta (GSK-3beta) [17].
• These results indicate that interaction between Dvl1 and receptor tyrosine kinase signal plays certain roles in developmental events [19].
• The Drosophila dishevelled gene (dsh) encodes a secreted glycoprotein, which regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification [20].
• In this study, using structure-based virtual ligand screening, we identified an organic molecule (NSC668036) from the National Cancer Institute small-molecule library that can bind to the Dvl PDZ domain [21].

Physical interactions of Dvl1

• Therefore, these results suggest that Idax functions as a negative regulator of the Wnt signaling pathway by directly binding to the PDZ domain of Dvl [22].
• Idax and Axin competed with each other for the binding to Dvl [22].
• CONCLUSION: Smad 3 binds all three known isoforms of Dishevelled and binds Dishevelled 1 in vivo [23].

Regulatory relationships of Dvl1

• Overexpression of the mouse dishevelled-1 protein inhibits GSK-3beta-mediated phosphorylation of tau in transfected mammalian cells [24].
• Taken together, these results suggest that Dvl induces cytoskeletal and morphologic rearrangements in neuronal differentiating N2A cells through a mechanism that cannot be attributed exclusively to modulation of GSK3beta or beta-catenin activity, but which does depend upon a DIX-domain/vesicle-association-dependent signaling pathway [3].
• Dishevelled promotes neurite outgrowth in neuronal differentiating neuroblastoma 2A cells, via a DIX-domain dependent pathway [3].
• We show that loss of function of Dishevelled-1 (Dvl1) mimics and enhances the Wnt7a phenotype in the cerebellum [25].

Other interactions of Dvl1

• Dvl1 had a broad expression, reminiscent of that of Celsr2, and may be involved in neural maintenance [26].
• Additional experiments with LiCl as an inhibitor of GSK-3beta kinase activity indicate that the step affected by betaarr1 is upstream of GSK-3beta and most likely at the level of Dvl [13].
• These results identify betaarr1 as a regulator of Dvl-dependent LEF transcription and suggest that betaarr1 might serve as an adapter molecule that can couple Frizzled receptors and perhaps other GPCRs to these important transcription pathways [13].
• Deletion analysis suggested that Dvl-association determinants within Axin were contained between residues 603 and 810 [27].
• Dvl is a key protein that transmits the Wnt signal to the canonical beta-catenin pathway and the noncanonical planar cell polarity (PCP) pathway [28].

Analytical, diagnostic and therapeutic context of Dvl1

• To demonstrate functional conservation of Dsh family proteins, two mouse homologs of Drosophila Dsh, Dvl-1 and Dvl-2, were biochemically characterized in mouse and Drosophila cell culture systems [29].
• Dishevelled is an important transducer of divergent Wnt pathways [14].
• Using immunofluorescence staining, confocal microscopy, and coimmunoprecipitation experiments, we show that dishevelled associates with actin fibers and focal adhesion plaques in metanephric mesenchymal cells [30].
• Immunohistochemistry showed that Dvl1 and EPS8 expression overlap in particular tissues during organogenesis [19].

References