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Gene Review

Dvl1  -  dishevelled, dsh homolog 1 (Drosophila)

Mus musculus

Synonyms: DSH homolog 1, Dishevelled-1, Dvl, Segment polarity protein dishevelled homolog DVL-1, mKIAA4029
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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


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


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


  1. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Hamblet, N.S., Lijam, N., Ruiz-Lozano, P., Wang, J., Yang, Y., Luo, Z., Mei, L., Chien, K.R., Sussman, D.J., Wynshaw-Boris, A. Development (2002) [Pubmed]
  2. Casein kinase 2 Is activated and essential for Wnt/beta-catenin signaling. Gao, Y., Wang, H.Y. J. Biol. Chem. (2006) [Pubmed]
  3. Dishevelled promotes neurite outgrowth in neuronal differentiating neuroblastoma 2A cells, via a DIX-domain dependent pathway. Fan, S., Ramirez, S.H., Garcia, T.M., Dewhurst, S. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  4. Human homologue sequences to the Drosophila dishevelled segment-polarity gene are deleted in the DiGeorge syndrome. Pizzuti, A., Novelli, G., Mari, A., Ratti, A., Colosimo, A., Amati, F., Penso, D., Sangiuolo, F., Calabrese, G., Palka, G., Silani, V., Gennarelli, M., Mingarelli, R., Scarlato, G., Scambler, P., Dallapiccola, B. Am. J. Hum. Genet. (1996) [Pubmed]
  5. cDNA cloning of a human dishevelled DVL-3 gene, mapping to 3q27, and expression in human breast and colon carcinomas. Bui, T.D., Beier, D.R., Jonssen, M., Smith, K., Dorrington, S.M., Kaklamanis, L., Kearney, L., Regan, R., Sussman, D.J., Harris, A.L. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  6. Expanded characterization of the social interaction abnormalities in mice lacking Dvl1. Long, J.M., LaPorte, P., Paylor, R., Wynshaw-Boris, A. Genes Brain Behav. (2004) [Pubmed]
  7. Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development. Kioussi, C., Briata, P., Baek, S.H., Rose, D.W., Hamblet, N.S., Herman, T., Ohgi, K.A., Lin, C., Gleiberman, A., Wang, J., Brault, V., Ruiz-Lozano, P., Nguyen, H.D., Kemler, R., Glass, C.K., Wynshaw-Boris, A., Rosenfeld, M.G. Cell (2002) [Pubmed]
  8. The DIX domain targets dishevelled to actin stress fibres and vesicular membranes. Capelluto, D.G., Kutateladze, T.G., Habas, R., Finkielstein, C.V., He, X., Overduin, M. Nature (2002) [Pubmed]
  9. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Wong, H.C., Bourdelas, A., Krauss, A., Lee, H.J., Shao, Y., Wu, D., Mlodzik, M., Shi, D.L., Zheng, J. Mol. Cell (2003) [Pubmed]
  10. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Rosso, S.B., Sussman, D., Wynshaw-Boris, A., Salinas, P.C. Nat. Neurosci. (2005) [Pubmed]
  11. Isolation and characterization of mouse dishevelled-3. Tsang, M., Lijam, N., Yang, Y., Beier, D.R., Wynshaw-Boris, A., Sussman, D.J. Dev. Dyn. (1996) [Pubmed]
  12. Genomic organization of mouse Dishevelled genes. Yang, Y., Lijam, N., Sussman, D.J., Tsang, M. Gene (1996) [Pubmed]
  13. beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Chen, W., Hu, L.A., Semenov, M.V., Yanagawa, S., Kikuchi, A., Lefkowitz, R.J., Miller, W.E. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  14. Dishevelled proteins regulate cell adhesion in mouse blastocyst and serve to monitor changes in Wnt signaling. Na, J., Lykke-Andersen, K., Torres Padilla, M.E., Zernicka-Goetz, M. Dev. Biol. (2007) [Pubmed]
  15. Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Luo, Z.G., Wang, Q., Zhou, J.Z., Wang, J., Luo, Z., Liu, M., He, X., Wynshaw-Boris, A., Xiong, W.C., Lu, B., Mei, L. Neuron (2002) [Pubmed]
  16. Stage-dependent Dishevelled-1 expression during mouse spermatogenesis suggests a role in regulating spermatid morphological changes. Ma, P., Wang, H., Guo, R., Ma, Q., Yu, Z., Jiang, Y., Ge, Y., Ma, J., Xue, S., Han, D. Mol. Reprod. Dev. (2006) [Pubmed]
  17. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules. Ciani, L., Krylova, O., Smalley, M.J., Dale, T.C., Salinas, P.C. J. Cell Biol. (2004) [Pubmed]
  18. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Funato, Y., Michiue, T., Asashima, M., Miki, H. Nat. Cell Biol. (2006) [Pubmed]
  19. Identification of EPS8 as a Dvl1-associated molecule. Inobe, M., Katsube, K., Miyagoe, Y., Nabeshima, Y., Takeda, S. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  20. cDNA characterization and chromosomal mapping of two human homologues of the Drosophila dishevelled polarity gene. Pizzuti, A., Amati, F., Calabrese, G., Mari, A., Colosimo, A., Silani, V., Giardino, L., Ratti, A., Penso, D., Calzà, L., Palka, G., Scarlato, G., Novelli, G., Dallapiccola, B. Hum. Mol. Genet. (1996) [Pubmed]
  21. Identification of a specific inhibitor of the dishevelled PDZ domain. Shan, J., Shi, D.L., Wang, J., Zheng, J. Biochemistry (2005) [Pubmed]
  22. Inhibition of the Wnt signaling pathway by Idax, a novel Dvl-binding protein. Hino, S., Kishida, S., Michiue, T., Fukui, A., Sakamoto, I., Takada, S., Asashima, M., Kikuchi, A. Mol. Cell. Biol. (2001) [Pubmed]
  23. Interaction between Smad 3 and Dishevelled in murine embryonic craniofacial mesenchymal cells. Warner, D.R., Greene, R.M., Pisano, M.M. Orthodontics & craniofacial research. (2005) [Pubmed]
  24. Overexpression of the mouse dishevelled-1 protein inhibits GSK-3beta-mediated phosphorylation of tau in transfected mammalian cells. Wagner, U., Brownlees, J., Irving, N.G., Lucas, F.R., Salinas, P.C., Miller, C.C. FEBS Lett. (1997) [Pubmed]
  25. Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release. Ahmad-Annuar, A., Ciani, L., Simeonidis, I., Herreros, J., Fredj, N.B., Rosso, S.B., Hall, A., Brickley, S., Salinas, P.C. J. Cell Biol. (2006) [Pubmed]
  26. Expression of planar cell polarity genes during development of the mouse CNS. Tissir, F., Goffinet, A.M. Eur. J. Neurosci. (2006) [Pubmed]
  27. Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. Smalley, M.J., Sara, E., Paterson, H., Naylor, S., Cook, D., Jayatilake, H., Fryer, L.G., Hutchinson, L., Fry, M.J., Dale, T.C. EMBO J. (1999) [Pubmed]
  28. Wnt-3a and Dvl induce neurite retraction by activating Rho-associated kinase. Kishida, S., Yamamoto, H., Kikuchi, A. Mol. Cell. Biol. (2004) [Pubmed]
  29. Characterization of mouse dishevelled (Dvl) proteins in Wnt/Wingless signaling pathway. Lee, J.S., Ishimoto, A., Yanagawa, S. J. Biol. Chem. (1999) [Pubmed]
  30. Colocalization and redistribution of dishevelled and actin during Wnt-induced mesenchymal morphogenesis. Torres, M.A., Nelson, W.J. J. Cell Biol. (2000) [Pubmed]
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