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.

Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion

Abstract

The Drosophila melanogaster gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian Alk, a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs)1. We have previously shown that the Drosophila Alk RTK is crucial for visceral mesoderm development during early embryogenesis2. Notably, observed Alk visceral mesoderm defects are highly reminiscent of the phenotype reported for the secreted molecule Jelly belly (Jeb)3. Here we show that Drosophila Alk is the receptor for Jeb in the developing visceral mesoderm, and that Jeb binding stimulates an Alk-driven, extracellular signal-regulated kinase-mediated signalling pathway, which results in the expression of the downstream gene duf (also known as kirre)4,5—needed for muscle fusion. This new signal transduction pathway drives specification of the muscle founder cells, and the regulation of Duf expression by the Drosophila Alk RTK explains the visceral-mesoderm-specific muscle fusion defects observed in both Alk and jeb mutant animals.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Jeb and Alk mutants show identical visceral mesoderm phenotypes.
Figure 2: Jeb and Alk are both required for activation of ERK and expression of Duf in muscle founder cells.
Figure 3: Jeb is taken up by Alk in the visceral mesoderm.
Figure 4: Alk kinase activity is required for the uptake of Jeb in the visceral mesoderm.

References

  1. Loren, C. E. et al. Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo. Genes Cells 6, 531–544 (2001)

    CAS  Article  Google Scholar 

  2. Loren, C. E. et al. A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster. EMBO Rep. 4, 781–786 (2003)

    CAS  Article  Google Scholar 

  3. Weiss, J. B., Suyama, K. L., Lee, H. H. & Scott, M. P. Jelly belly: a Drosophila LDL receptor repeat-containing signal required for mesoderm migration and differentiation. Cell 107, 387–398 (2001)

    CAS  Article  Google Scholar 

  4. Ruiz-Gomez, M., Coutts, N., Price, A., Taylor, M. V. & Bate, M. Drosophila dumbfounded: a myoblast attractant essential for fusion. Cell 102, 189–198 (2000)

    CAS  Article  Google Scholar 

  5. Strunkelnberg, M. et al. rst and its paralogue kirre act redundantly during embryonic muscle development in Drosophila. Development 128, 4229–4239 (2001)

    CAS  PubMed  Google Scholar 

  6. Fujimoto, J. et al. Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc. Natl Acad. Sci. USA 93, 4181–4186 (1996)

    ADS  CAS  Article  Google Scholar 

  7. Morris, S. W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263, 1281–1284 (1994)

    ADS  CAS  Article  Google Scholar 

  8. Falini, B. Anaplastic large cell lymphoma: pathological, molecular and clinical features. Br. J. Haematol. 114, 741–760 (2001)

    CAS  Article  Google Scholar 

  9. Duyster, J., Bai, R. Y. & Morris, S. W. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20, 5623–5637 (2001)

    CAS  Article  Google Scholar 

  10. Morris, S. W. et al. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 14, 2175–2188 (1997)

    CAS  Article  Google Scholar 

  11. Iwahara, T. et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14, 439–449 (1997)

    CAS  Article  Google Scholar 

  12. Klapper, R. et al. The formation of syncytia within the visceral musculature of the Drosophila midgut is dependent on duf, sns and mbc. Mech. Dev. 110, 85–96 (2002)

    CAS  Article  Google Scholar 

  13. Martin, B. S., Ruiz-Gomez, M., Landgraf, M. & Bate, M. A distinct set of founders and fusion-competent myoblasts make visceral muscles in the Drosophila embryo. Development 128, 3331–3338 (2001)

    CAS  PubMed  Google Scholar 

  14. Dworak, H. A. & Sink, H. Myoblast fusion in Drosophila. Bioessays 24, 591–601 (2002)

    CAS  Article  Google Scholar 

  15. Baylies, M. K. & Michelson, A. M. Invertebrate myogenesis: looking back to the future of muscle development. Curr. Opin. Genet. Dev. 11, 431–439 (2001)

    CAS  Article  Google Scholar 

  16. Bate, M. The embryonic development of larval muscles in Drosophila. Development 110, 791–804 (1990)

    CAS  PubMed  Google Scholar 

  17. Carmena, A., Bate, M. & Jimenez, F. Lethal of scute, a proneural gene, participates in the specification of muscle progenitors during Drosophila embryogenesis. Genes Dev. 9, 2373–2383 (1995)

    CAS  Article  Google Scholar 

  18. Gabay, L., Seger, R. & Shilo, B. Z. MAP kinase in situ activation atlas during Drosophila embryogenesis. Development 124, 3535–3541 (1997)

    CAS  PubMed  Google Scholar 

  19. Patel, N. H. Imaging neuronal subsets and other cell types in whole-mount Drosophila embryos and larvae using antibody probes. Methods Cell Biol. 44, 445–487 (1994)

    CAS  Article  Google Scholar 

  20. Campos-Ortega, J. A. & Hartenstein, V. The Embryonic Development of Drosophila Melanogaster. (Springer, Berlin, 1997)

  21. Palmer, R. H. et al. DFak56 is a novel Drosophila melanogaster focal adhesion kinase. J. Biol. Chem. 274, 35621–35629 (1999)

    CAS  Article  Google Scholar 

  22. Jiang, W. et al. PRC1: a human mitotic spindle-associated CDK substrate protein required for cytokinesis. Mol. Cell 2, 877–885 (1998)

    CAS  Article  Google Scholar 

  23. Kopczynski, C. C., Davis, G. W. & Goodman, C. S. A neural tetraspanin, encoded by late bloomer, that facilitates synapse formation. Science 271, 1867–1870 (1996)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank T. Hunter and I. Salecker for critical reading of the manuscript, and D. Eriksson, N. Norgren and A. Sheikholvaezin for help with ELISA analysis. This work is funded by the Swedish Research Council and is also supported by The Swedish Society for Medical Research (SSMF), Åke Wibergs Fund, the Royal Swedish Academy of Sciences, Lars Hiertas Minne Fund, and the Cancer Research Fund of Northern Sweden. F.D. was supported by a post-doctoral fellowship from the Wenner-Grenska Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ruth H. Palmer.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Englund, C., Lorén, C., Grabbe, C. et al. Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion. Nature 425, 512–516 (2003). https://doi.org/10.1038/nature01950

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01950

Further reading

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