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:

Serrate2 is disrupted in the mouse limb-development mutant syndactylism

Nature volume 389, pages 722–725 (1997)Cite this article

Abstract

The mouse syndactylism ( sm ) mutation impairs some of the earliest aspects of limb development and leads to subsequent abnormalities in digit formation1,2,3. In sm homozygotes, the apical ectodermal ridge (AER) is hyperplastic by embryonic day 10.5, leading to abnormal dorsoventral thickening of the limb bud, subsequent merging of the skeletal condensations that give rise to cartilage and bone in the digits, and eventual fusion of digits. The AER hyperplasia and its effect on early digital patterning distinguish sm from many other syndactylies that result from later failure of cell death in the interdigital areas4,5. Here we use positional cloning to show that the gene mutated in sm mice encodes the putative Notch ligand Serrate2. The results provide direct evidence that a Notch signalling pathway is involved in the earliest stages of limb-bud patterning and support the idea that an ancient genetic mechanism underlies both AER formation in vertebrates and wing-margin formation in flies6,7. In addition to cloning the sm gene, we have mapped three modifiers of sm, for which we suggest possible candidate genes.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: a Skeletal preparations of an sm -homozygous ( sm/sm ) hind foot and a wild-type (+/+) hind foot stained by Alizarin red.
Figure 2: Genetic and physical maps of the Serrate2 region.
Figure 3: a, Expression of Serrate2 in the AER, other areas of the limb ectoderm, and somites (arrowheads) in the E110 embryo.
Figure 4: Results from genome scan for suppressors and enhancers in the sm mapping cross.

Similar content being viewed by others

References

  1. Grüneberg, H. Genetical studies on the skeleton of the mouse. XVIII. Three genes for syndactylism. J. Genet. 54, 113–145 (1956).

    Google Scholar 

  2. Grüneberg, H. Genetical studies on the skeleton of the mouse. XXV. The development of syndactylism. Genet. Res. 1, 196–213 (1960).

    Google Scholar 

  3. Milaire, J. Histochemical observations on the developing foot of normal, oligosyndactylous (Os/+) and syndactylous (sm/sm) mouse embryos. Arch. Biol. 78, 223–288 (1967).

    Google Scholar 

  4. Lyon, M. F., Rastan, S. & Brown, S. D. B. (eds Genetic Variants and Strains of the Laboratory Mouse3rded (Oxford Univ. Press, 1996).

    Google Scholar 

  5. v.d.Hoeven, F. et al. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 120, 2601–2607 (1994).

    Google Scholar 

  6. Rodriguez-Esteban, C. et al. Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature 386, 360–366 (1997).

    Article  ADS  CAS  Google Scholar 

  7. Laufer, E. et al. Expression of Radical fringe in limb bud ectoderm regulates apical ectodermal ridge formation. Nature 386, 366–373 (1997).

    Article  ADS  CAS  Google Scholar 

  8. Nye, J. S. & Kopan, R. Vertebrate ligands for Notch. Curr. Biol. 5, 966–969 (1995).

    Google Scholar 

  9. Lindsell, C. E., Shawber, C. J., Boulter, J. & Weinmaster, G. Jagged: A mammalian ligand that activates Notch1. Cell 80, 909–917 (1995).

    Google Scholar 

  10. Shawber, C. J., Boulter, J., Lindsell, C. E. & Weinmaster, G. Jagged2: A Serrate-like gene expressed during rat embryogenesis. Dev. Biol. 180, 370–376 (1996).

    Google Scholar 

  11. Tax, F. E., Yeargers, J. J. & Thomas, J. H. Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila . Nature 368, 150–153 (1994).

    Article  ADS  CAS  Google Scholar 

  12. Montelione, G. T. et al. Solution structure of murine epidermal growth factor determined by NMR spectroscopy and refined by energy minimization with restraints. Biochemistry 31, 236–249 (1992).

    Google Scholar 

  13. Kelley, M. R., Kidd, S., Deutsch, W. A. & Young, M. W. Mutations altering the structure of epidermal growth factor-like coding sequences at the Drosophila Notch locus. Cell 51, 539–548 (1987).

    Google Scholar 

  14. Leiber, T. et al. Single amino acid substitutions in EGF-like elements of Notch and Delta modify Drosophila development and affect cell adhesion in vitro. Neuron 9, 847–859 (1992).

    Google Scholar 

  15. Xu, T., Caron, L. A., Fehon, R. G. & Artavanis-Tsakonas, S. The involvement of the Notch locus in Drosophila oogenesis. Development 115, 913–922 (1992).

    Google Scholar 

  16. Mouse Genome Database (MGD), Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine.World Wide Web URL: (http://www.informatics.jax.org/). (4/97).

  17. Johnson, D. R. Polysyndactyly, a new mutant gene in the mouse. J. Embryol. Exp. Morphol. 21, 285–294 (1969).

    Google Scholar 

  18. Jarriault, S. et al. Signalling downstream of activated mammalian Notch. Nature 377, 355–358 (1995).

    Article  ADS  CAS  Google Scholar 

  19. Panin, V. P., Papayannopoulos, V., Wilson, R. & Irvine, K. D. Fringe modulates Notch–ligand interactions. Nature 387, 908–912 (1997).

    Article  ADS  CAS  Google Scholar 

  20. Dietrich, W. F. et al. Acomprehensive genetic map of the mouse genome. Nature 380, 149–152 (1996).

    Article  ADS  CAS  Google Scholar 

  21. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning (CSH Lab. Press, New York, 1989).

    Google Scholar 

  22. Wilkinson, D. (ed. In Situ Hybridization: A Practical Approach. (IRL, Oxford, 1992).

    Google Scholar 

  23. Sidow, A. & Thomas, W. K. Amolecular evolutionary framework for eukaryotic model organisms. Curr. Biol. 4, 596–603 (1994).

    Google Scholar 

Download references

Acknowledgements

We thank J. Dausman, R. Curry and P. Ros for help with mice; Z. Husain, K. Devon, K. Harris, J. Williams, E. Sun, G. Farino, C. Munro and V. van Berkel for technical assistance; J. Segre, K. Kusumi, L. Kruglyak and B. Parr for technical advice; M. Hosobuchi, D. Fambrough, B. Hamilton and K. Kusumi for comments on the manuscript. This work was supported by a postdoctoral fellowship from the Helen Hay Whitney Foundation to A.S., and by NIH grants to E.S.L., B.L.B., T.L.H. and R.T.B.

Author information

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Arend Sidow, Monique S. Bulotsky, Anne W. Kerrebrock, Mark J. Daly, Mary P. Reeve, Trevor L. Hawkins, Bruce W. Birren, Rudolf Jaenisch & Eric S. Lander

  2. Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, 02111, Massachusetts, USA

    Roderick T. Bronson

Authors
  1. Arend Sidow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monique S. Bulotsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anne W. Kerrebrock
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roderick T. Bronson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark J. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mary P. Reeve
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Trevor L. Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruce W. Birren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rudolf Jaenisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eric S. Lander
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric S. Lander.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sidow, A., Bulotsky, M., Kerrebrock, A. et al. Serrate2 is disrupted in the mouse limb-development mutant syndactylism. Nature 389, 722–725 (1997). https://doi.org/10.1038/39587

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/39587

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

Advanced 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