Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Scrambler and yotari disrupt the disabled gene and produce a reeler -like phenotype in mice

Abstract

Formation of the mammalian brain requires choreographed migration of neurons to generate highly ordered laminar structures such as those in the cortices of the forebrain and the cerebellum. These processes are severely disrupted by mutations in reelin1 which cause widespread misplacement of neurons and associated ataxia in reeler mice2,3. Reelin is a large extracellular protein secreted by pioneer neurons that coordinates cell positioning during neurodevelopment1,4,5,6,7,8. Two new autosomal recessive mouse mutations, scrambler9 and yotari10 have been described that exhibit a phenotype identical to reeler9,10,11. Here we report that scrambler and yotari arise from mutations in mdab1 (ref. 12), a mouse gene related to the Drosophila gene disabled ( dab )13. Both scrambler and yotari mice express mutated forms of mdab1 messenger RNA and little or no mDab1 protein. mDab1 is a phosphoprotein that appears to function as an intracellular adaptor in protein kinase pathways. Expression analysis indicates that mdab1 is expressed in neuronal populations exposed to Reelin. The similar phenotypes of reeler, scrambler, yotari and mdab1 null mice14 indicate that Reelin and mDab1 function as signalling molecules that regulate cell positioning in the developing brain.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Reelin is expressed normally in scrambler.
Figure 2: Expression of mdab1 mRNA in scrambler and yotari.
Figure 3: Analysis of mDab1 protein expression.
Figure 4: Distribution of mdab1 and reelin mRNA in E13.

Similar content being viewed by others

References

  1. D'Arcangelo, G. et al. Aprotein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719–723 (1995).

    Article  ADS  CAS  Google Scholar 

  2. Goffinet, A. M. Areal gene for reeler. Nature 374, 675–676 (1995).

    Article  ADS  CAS  Google Scholar 

  3. Rakic, P. & Caviness, V. S. J. Cortical development: view from neurological mutants two decades later. Neuron 14, 1101–1104 (1995).

    Google Scholar 

  4. D'Arcangelo, G. et al. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J. Neurosci. 17, 23–31 (1997).

    Google Scholar 

  5. Hirotsune, S. et al. The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons. Nature Genet. 10, 77–83 (1995).

    Google Scholar 

  6. Ogawa, M. et al. The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14, 899–912 (1995).

    Google Scholar 

  7. Miyata, T. et al. Distribution of the reeler gene-related antigen in the developing cerebellum: an immunohistochemical study with an allogenic antibody CR-50 on normal and reeler mice. J. Comp. Neurol. 372, 215–228 (1996).

    Google Scholar 

  8. Miyata, T., Nakajima, K., Mikoshiba, K. & Ogawa, M. Regulation of purkinje cell alignment by reelin as revealed with R-50 antibody. J. Neurosci. 17, 3599–3609 (1997).

    Google Scholar 

  9. Sweet, H. O., Bronson, R. T., Johnson, K. R., Cook, S. A. & Davisson, M. T. Scrambler, a new neurological mutation of the mouse with abnormalities of neuronal migration Mamm . Genome 7, 798–802 (1996).

    Google Scholar 

  10. Yoneshima, H. et al. Anovel neurological mutation of mouse, yotari, which has reeler -like phenotype but expresses reelin. Neurosci. Res. (in the press).

  11. Goldowitz, D. et al. Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of reelin. J. Neurosci. (in the press).

  12. Howell, B. W., Gertler, F. B. & Cooper, J. A. Mouse disabled (mDab1): a src binding protein implicated in neuronal development. EMBO J. 16, 121–132 (1997).

    Google Scholar 

  13. Gertler, F. B., Bennett, R. L., Clark, M. J. & Hoffmann, F. M. Drosophila abl tyrosine kinase in embryonic CNS axons: a role in axogenesis is revealed through dosage-sensitive interactions with disabled . Cell 58, 103–113 (1989).

    Google Scholar 

  14. Howell, B. W., Hawkes, R., Soriano, P. & Cooper, J. A. Neuronal position in the developing brain is regulated by mouse disabled-1 . Nature 389, 733–737 (1997).

    Article  ADS  CAS  Google Scholar 

  15. Tartaglia, L. A. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    Google Scholar 

  16. Chua, S. C. J et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271, 994–996 (1996).

    Google Scholar 

  17. Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    Article  ADS  CAS  Google Scholar 

  18. Michaud, E. J. et al. Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev. 8, 1463–1472 (1994).

    Google Scholar 

  19. Rowe, L. B. et al. Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm. Genome 5, 253–274 (1994).

    Google Scholar 

  20. Goffinet, A. M. Events governing organization of postmigratory neurons: studies on brain development in normal and reeler mice. Brain Res. Rev. 7, 261–296 (1984).

    Google Scholar 

  21. Xu, X. X., Yang, W., Jackowski, S. & Rock, C. O. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J. Biol. Chem. 270, 14184–14191 (1995).

    Google Scholar 

  22. Zhou, M. M. et al. Structure and ligand recognition of the phosphotyrosine binding domain of Sch. Nature 378, 584–592 (1995).

    Article  ADS  CAS  Google Scholar 

  23. Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173–11178 (1996).

    Google Scholar 

  24. Chae, T. et al. Mice lacking p35, a neuronal activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 (1997).

    Google Scholar 

  25. Tang, D. et al. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J. Biol. Chem. 270, 26897–26903 (1995).

    Google Scholar 

  26. Del Rio, J. A. et al. Arole for Cajal-Retzius cells and reelin in the development of hippocampal connections. Nature 385, 70–74 (1997).

    Article  ADS  CAS  Google Scholar 

  27. Vaessin, H. et al. prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila . Cell 67, 941–953 (1991).

    Google Scholar 

  28. Oliver, G. et al. Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech. Dev. 44, 3–16 (1993).

    Google Scholar 

  29. Gertler, F. B. et al. enabled, a dosage-sensitive suppressor of mutations in the Drosophila Abl tyrosine kinase, encodes an Abl substrate with SH3 domain-binding properties. Genes Dev. 9, 521–533 (1995).

    Google Scholar 

  30. Gertler, F. B., Niebuhr, K., Reinhard, M., Wehland, J. & Soriano, P. Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics. Cell 87, 227–239 (1996).

    Google Scholar 

  31. Dietrich, W. F. et al. Agenetic map of the mouse with 4,006 simple sequence length polymorphisms. Nature Genet. 7, 220–245 (1994).

    Google Scholar 

Download references

Acknowledgements

We thank L.-Y. Kung for technical assistance in PCR genotyping; R. Smeyne for discussions; and K. Johnson and M. Davisson for mapping reagents. This work was supported in part by an NIH Cancer Center Support CORE grant, a grant from the NINDS (T.C.), the American Lebanese Syrian Associated Charities (ALSAC), NRSA from NCI (M.S.), NRSA from NINDS (G.D.), the University of Tennessee and the Department of Anatomy and Neurobiology, the Science and Technology Agency of the Japanese Government, and the Ministry of Education, Science and Culture of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tom Curran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sheldon, M., Rice, D., D'Arcangelo, G. et al. Scrambler and yotari disrupt the disabled gene and produce a reeler -like phenotype in mice. Nature 389, 730–733 (1997). https://doi.org/10.1038/39601

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/39601

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing