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Gene Review

Dab1  -  disabled 1

Mus musculus

Synonyms: AI956902, C630028C02Rik, Disabled homolog 1, scm, scr, ...
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Disease relevance of Dab1

  • A distal Dab1 cell had been reported in the FVB/N mouse retina, a model of retinitis pigmentosa (Park et al. [2004] Cell Tissue Res 315:407-412) [1].

Psychiatry related information on Dab1


High impact information on Dab1

  • The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices [4].
  • These results suggest that Reln regulates neuronal positioning by stimulating Dab1 tyrosine phosphorylation [5].
  • Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway [6].
  • Addition of Reelin interfering antibodies, receptor antagonists, and Dab1 phosphorylation inhibitors prevented dendrite outgrowth from normal neurons, whereas addition of recombinant Reelin rescued the deficit in reeler cultures [6].
  • However, in the reeler background, ectopic Reelin induced tyrosine phosphorylation of Dab-1 in the ventricular zone and rescued some, but not all, of the neuroanatomic and behavioral abnormalities characteristic of reeler [7].

Biological context of Dab1


Anatomical context of Dab1

  • During development, cells expressing Dab1 are located next to those secreting Reln at critical stages of formation of the cerebral cortex, cerebellum and hippocampus, before the first abnormalities in cell position become apparent in either reeler or scrambler [8].
  • Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain [13].
  • In the double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus [14].
  • Moreover, Dab1 did not stably associate with the receptors at the plasma membrane in the resting state [15].
  • Dab1 is a key cytoplasmic mediator in Reelin signaling that controls cell positioning in the developing central nervous system, whereas Dab2 is an adapter protein that plays a role in endocytosis [16].

Associations of Dab1 with chemical compounds

  • Although the functional significance of Dab1 serine phosphorylation is unclear, our results suggest that there is biochemical cross-talk between two signaling pathways that control cell positioning [17].
  • Dab1 co-localizes with the high-affinity glycine transporter, indicating that these amacrine cells are glycinergic [18].
  • Reelin is a secreted glycoprotein that regulates neuronal positioning in cortical brain structures through the VLDLR and ApoER2 receptors and the adaptor protein Dab1 [6].
  • Mutated Reelin, which lacks the CR-50 epitope region, cannot form a homopolymer and fails to induce efficient tyrosine phosphorylation of Disabled 1 (Dab1), which should occur to transduce the Reelin signal [19].
  • Dab1 molecules lacking phosphotyrosine are not degraded in neurons in which the Dab1 degradation pathway is active [20].

Enzymatic interactions of Dab1

  • When fyn copy number is reduced, src, but not yes, becomes important, reflecting a partial redundancy between fyn and src.CONCLUSIONS: Reelin activates Fyn to phosphorylate and downregulate Dab1 during brain development [21].

Regulatory relationships of Dab1

  • Binding of Reelin to ApoER2 and VLDLR induces a rapid increase in tyrosine phosphorylation of Dab1, an adaptor protein that associates with the cytoplasmic domain of the receptors [22].
  • Using pharmacological inhibitors and mice harboring mutant alleles of Dab1, we show here that tyrosine phosphorylation, but not the carboxyl-terminal region, of Dab1 is required for Reelin-induced activation of Akt and Src family kinases [23].
  • Additionally, we detected neurokinin-1 receptors expressed by Dab1-labeled neurons in reeler laminae I-III and the lateral spinal nucleus [24].

Other interactions of Dab1

  • We have found that the intracellular Dab1 protein receives a tyrosine phosphorylation signal from extracellular Reln protein [5].
  • We have generated mutant mice that express only a natural splice form of Dab1, p45, that lacks the C-terminal region of p80 [25].
  • The results were unexpected because Fyn deficiency does not cause the same developmental phenotype as Dab1 or Reelin deficiency [21].
  • Overexpression of CrkIIGFP rescued the migration of these cells, suggesting that Dab1 makes Crk a limiting factor for migration [26].
  • Reelin binds to transmembrane receptors, including VLDLR and ApoER2, and stimulates tyrosine phosphorylation of Disabled-1 (Dab1), which associates with an NPxY motif present in the cytoplasmic domain of the receptors [18].

Analytical, diagnostic and therapeutic context of Dab1


  1. AII amacrine cells in the distal inner nuclear layer of the mouse retina. Lee, E.J., Mann, L.B., Rickman, D.W., Lim, E.J., Chun, M.H., Grzywacz, N.M. J. Comp. Neurol. (2006) [Pubmed]
  2. Genetic modulation of tau phosphorylation in the mouse. Brich, J., Shie, F.S., Howell, B.W., Li, R., Tus, K., Wakeland, E.K., Jin, L.W., Mumby, M., Churchill, G., Herz, J., Cooper, J.A. J. Neurosci. (2003) [Pubmed]
  3. Identification of disabled-1 as a candidate gene for critical period neuroplasticity in cat and mouse visual cortex. Yang, C.B., Zheng, Y.T., Kiser, P.J., Mower, G.D. Eur. J. Neurosci. (2006) [Pubmed]
  4. Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression. Chang, Y., Ostling, P., Akerfelt, M., Trouillet, D., Rallu, M., Gitton, Y., El Fatimy, R., Fardeau, V., Le Crom, S., Morange, M., Sistonen, L., Mezger, V. Genes Dev. (2006) [Pubmed]
  5. Reelin-induced tryosine phosphorylation of disabled 1 during neuronal positioning. Howell, B.W., Herrick, T.M., Cooper, J.A. Genes Dev. (1999) [Pubmed]
  6. Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway. Niu, S., Renfro, A., Quattrocchi, C.C., Sheldon, M., D'Arcangelo, G. Neuron (2004) [Pubmed]
  7. Rescue of ataxia and preplate splitting by ectopic expression of Reelin in reeler mice. Magdaleno, S., Keshvara, L., Curran, T. Neuron (2002) [Pubmed]
  8. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Rice, D.S., Sheldon, M., D'Arcangelo, G., Nakajima, K., Goldowitz, D., Curran, T. Development (1998) [Pubmed]
  9. Identification of reelin-induced sites of tyrosyl phosphorylation on disabled 1. Keshvara, L., Benhayon, D., Magdaleno, S., Curran, T. J. Biol. Chem. (2001) [Pubmed]
  10. Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Howell, B.W., Herrick, T.M., Hildebrand, J.D., Zhang, Y., Cooper, J.A. Curr. Biol. (2000) [Pubmed]
  11. Signaling through Disabled 1 requires phosphoinositide binding. Huang, Y., Shah, V., Liu, T., Keshvara, L. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  12. Tyrosine phosphorylated Disabled 1 recruits Crk family adapter proteins. Huang, Y., Magdaleno, S., Hopkins, R., Slaughter, C., Curran, T., Keshvara, L. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  13. Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain. Ohshima, T., Ogawa, M., Takeuchi, K., Takahashi, S., Kulkarni, A.B., Mikoshiba, K. J. Neurosci. (2002) [Pubmed]
  14. Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain. Ohshima, T., Ogawa, M., Veeranna, n.u.l.l., Hirasawa, M., Longenecker, G., Ishiguro, K., Pant, H.C., Brady, R.O., Kulkarni, A.B., Mikoshiba, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  15. Disabled1 regulates the intracellular trafficking of reelin receptors. Morimura, T., Hattori, M., Ogawa, M., Mikoshiba, K. J. Biol. Chem. (2005) [Pubmed]
  16. Crystal structures of the Dab homology domains of mouse disabled 1 and 2. Yun, M., Keshvara, L., Park, C.G., Zhang, Y.M., Dickerson, J.B., Zheng, J., Rock, C.O., Curran, T., Park, H.W. J. Biol. Chem. (2003) [Pubmed]
  17. Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling. Keshvara, L., Magdaleno, S., Benhayon, D., Curran, T. J. Neurosci. (2002) [Pubmed]
  18. Disabled-1 is expressed in type AII amacrine cells in the mouse retina. Rice, D.S., Curran, T. J. Comp. Neurol. (2000) [Pubmed]
  19. Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody. Utsunomiya-Tate, N., Kubo, K., Tate, S., Kainosho, M., Katayama, E., Nakajima, K., Mikoshiba, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  20. Regulation of protein tyrosine kinase signaling by substrate degradation during brain development. Arnaud, L., Ballif, B.A., Cooper, J.A. Mol. Cell. Biol. (2003) [Pubmed]
  21. Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Arnaud, L., Ballif, B.A., Förster, E., Cooper, J.A. Curr. Biol. (2003) [Pubmed]
  22. Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Benhayon, D., Magdaleno, S., Curran, T. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  23. Tyrosine phosphorylation of Disabled-1 is essential for Reelin-stimulated activation of Akt and Src family kinases. Ballif, B.A., Arnaud, L., Cooper, J.A. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  24. Absence of Reelin results in altered nociception and aberrant neuronal positioning in the dorsal spinal cord. Villeda, S.A., Akopians, A.L., Babayan, A.H., Basbaum, A.I., Phelps, P.E. Neuroscience (2006) [Pubmed]
  25. A hypomorphic allele of dab1 reveals regional differences in reelin-Dab1 signaling during brain development. Herrick, T.M., Cooper, J.A. Development (2002) [Pubmed]
  26. Interaction between Dab1 and CrkII is promoted by Reelin signaling. Chen, K., Ochalski, P.G., Tran, T.S., Sahir, N., Schubert, M., Pramatarova, A., Howell, B.W. J. Cell. Sci. (2004) [Pubmed]
  27. The dual-function disabled-1 PTB domain exhibits site independence in binding phosphoinositide and peptide ligands. Stolt, P.C., Vardar, D., Blacklow, S.C. Biochemistry (2004) [Pubmed]
  28. Morphological analysis of disabled-1-immunoreactive amacrine cells in the guinea pig retina. Lee, E.J., Kim, H.J., Kim, I.B., Park, J.H., Oh, S.J., Rickman, D.W., Chun, M.H. J. Comp. Neurol. (2003) [Pubmed]
  29. Inhibition of ubiquitin ligase Siah-1A by disabled-1. Park, T.J., Hamanaka, H., Ohshima, T., Watanabe, N., Mikoshiba, K., Nukina, N. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
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