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.

  • Article
  • Published:

Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2

Nature Cell Biology volume 2, pages 515–520 (2000)Cite this article

Abstract

Proteins encoded by the fringe family of genes are required to modulate Notch signalling in a wide range of developmental contexts. Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1-mediated signalling and potentiates Delta1-mediated signalling through Notch1. Lfng localizes to the Golgi, and Lfng-dependent modulation of Notch signalling requires both expression of Lfng in the Notch-responsive cell and the Notch extracellular domain. Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1-expressing cells. Lfng potentiates both Jagged1- and Delta1-mediated signalling via Notch2, in contrast to its actions with Notch1. Our data suggest that Fringe-dependent differential modulation of the interaction of Delta/Serrate/Lag2 (DSL) ligands with their Notch receptors is likely to have a significant role in the combinatorial repertoire of Notch signalling in mammals.

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: Mammalian Fringe proteins modulate ligand-induced Notch1 signalling in mouse myoblasts and fibroblasts.
Figure 2: Lfng functions in the Notch1-expressing cell.
Figure 3: Immunolocalization of Lfng and Mfng proteins expressed in stable cell lines.
Figure 4: Lfng does not modulate constitutive signalling from ligand-independent forms of Notch1.
Figure 5: Lfng does not inhibit Jag1Fc binding to Notch1.
Figure 6: Lfng does not inhibit Jagged1-induced Notch2 signalling.

Similar content being viewed by others

References

  1. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signalling: cell fate control and signal integration in development. Science 284, 770-776 (1999).

    Article  Google Scholar 

  2. Kuroda, K. et al. Delta-induced Notch signalling mediated by RBP-J inhibits MyoD expression and myogenesis. J. Biol. Chem. 274, 7238–7244 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Jarriault, S. et al. Delta-1 activation of notch-1 signalling results in HES-1 transactivation. Mol. Cell. Biol. 18, 7423 –7431 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Li, L. et al. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity 8, 43–55 ( 1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Nofziger, D., Miyamoto, A., Lyons, K. M. & Weinmaster, G. Notch signalling imposes two distinct blocks in the differentiation of C2C12 myoblasts. Development 126, 1689– 1702 (1999).

    CAS  PubMed  Google Scholar 

  7. Luo, B., Aster, J. C., Hasserjian, R. P., Kuo, F. & Sklar, J. Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol. Cell. Biol. 17, 6057–6067 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  9. Lindsell, C. E., Boutler, J., diSibio, G., Gossler, A. & Weinmaster, G. Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol. Cell. Neurosci. 8, 14– 27 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Blair, S. S. Limb development: Marginal fringe benefits. Curr. Biol. 7, R686–R690 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Irvine, K. D. Fringe, Notch, and making developmental boundaries. Curr. Opin. Genet. Dev. 9, 434–441 ( 1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Fleming, R. J., Gu, Y. & Hukriede, N. A. Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124, 2973 –2981 (1997).

    CAS  PubMed  Google Scholar 

  14. Johnston, S. H. et al. A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development 124 , 2245–2254 (1997).

    CAS  PubMed  Google Scholar 

  15. Cohen, B. et al. Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nature Genet. 16, 283–288 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. May, W. A. et al. EWS/FLI 1-induced manic fringe renders NIH3T3 cells tumorigenic . Nature Genet. 17, 495– 497 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Wu, J. Y., Wen, L., Zhang, W. J. & Rao, Y. The secreted product of Xenopus gene lunatic fringe, a vertebrate signalling molecule. Science 273, 355–358 ( 1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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  CAS  PubMed  Google Scholar 

  20. Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377– 381 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Barrantes, I. B. et al. Interaction between Notch signalling and Lunatic fringe during somite boundary formation in the mouse. Curr. Biol. 9, 470–480 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, N. & Gridley, T. Defects in somite formation in lunatic fringe-deficient mice. Nature 394, 374– 377 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  24. Wong, P. C. et al. Presenilin1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387, 288– 292 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Irvine, K. D. & Wieschaus, E. Fringe, a boundary-specific signalling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79, 595– 606 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Yuan, Y. P., Schultz, J., Mlodzik, M. & Bork, P. Secreted fringe-like signalling molecules may be glycosyltransferases. Cell 88, 9–11 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Shima, D. T., Haldar, K., Pepperkok, R., Watson, R. & Warren, G. Partitioning of the Golgi apparatus during mitosis in living HeLa cells. J. Cell. Biol. 137, 1211–1228 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Waters, M. G., Clary, D. O. & Rothman, J. E. A novel 115-kD peripheral membrane protein is required for intercisternal transport in the Golgi stack. J. Cell. Biol. 118, 1015–1026 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  29. Shawber, C. et al. Notch signalling inhibits muscle cell differentiation through a CBF1-independent pathway. Development 122, 3765–3773 (1996).

    CAS  PubMed  Google Scholar 

  30. Hukriede, N. A., Gu, Y. & Fleming, R. J. A dominant-negative form of Serrate acts as a general antagonist of Notch activation. Development 124, 3427–3437 (1997).

    CAS  PubMed  Google Scholar 

  31. Panin, V. M. & Irvine, K. D. Modulators of Notch signalling . Semin. Cell. Dev. Biol. 9, 609– 617 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Shimizu, K. et al. Mouse Jagged1 physically interacts with Notch2 and other Notch receptors. Assessment by quantitative methods. J. Biol. Chem. 274, 32961–32969 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Sestan, N., Artavanis-Tsakonas, S. & Rakic, P. Contact-dependent inhibition of cortical neurite growth mediated by notch signalling. Science 286, 741–746 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Qi, H. et al. Processing of the Notch ligand Delta by the metalloprotease Kuzbanian . Science 283, 91–94 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, S. et al. Notch receptor activation inhibits oligodendrocyte differentiation . Neuron 21, 63–75 (1998).

    Article  PubMed  Google Scholar 

  36. Varnum-Finney, B. et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91, 4084–4091 (1998).

    CAS  PubMed  Google Scholar 

  37. Weinmaster, G. The ins and outs of notch signalling. Mol. Cell. Neurosci. 9, 91–102 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Moloney, D. J. et al. Mammalian Notch1 is modified with two unusual forms of O-linked glycosylation found on epidernal growth factor-like modules. J. Biol. Chem. 275, 9604–9611 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Kusumi, K. et al. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature Genet. 19, 274–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Hrabe de Angelis, M., McIntyre, J. N. & Gossler, A. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386, 717– 721 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Conlon, R. A., Reaume, A. G. & Rossant, J. Notch1 is required for the coordinate segmentation of somites. Development 121, 1533– 1545 (1995).

    CAS  PubMed  Google Scholar 

  42. Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G. & Gridley, T. Notch1 is essential for postimplantation development in mice. Genes Dev. 8, 707– 719 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Heitzler, P. & Simpson, P. Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions. Development 117, 1113– 1123 (1993).

    CAS  PubMed  Google Scholar 

  44. Klueg, K. M. & Muskavitch, M. A. Ligand-receptor interactions and trans-endocytosis of Delta, Serrate and Notch: members of the Notch signalling pathway in Drosophila. J. Cell Sci. 112, 3289–3297 (1999).

    CAS  PubMed  Google Scholar 

  45. De Strooper, B. et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Schroeter, E., Kisslinger, J. & Kopan, R. Notch1 signalling requires ligand-induced proteolytic release of the intracellular domain. Nature 393, 382–386 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Brou, C. et al. A novel proteolytic cleavage involved in Notch signalling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5, 207–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Mumm, J. S. et al. A ligand-induced extracellular cleavage regulates γ-secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197–206 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. MacArthur, C. A. et al. FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. Development 121, 3603-3613 (1995).

    Google Scholar 

  50. Hsieh, J. J. et al. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA 2. Mol. Cell. Biol. 16, 952-959 ( 1996).

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank K. Irvine, A. Van der Bliek, E. Robey and G. Waters for critical and insightful comments on this work and K. Irvine, R. Haltiwanger and P. Stanley for communicating data before publication. We are also indebted to S. Ting-Berreth, T. Covey, C. MacArthur, G. Waters, D. Hayward, and J. Flanagan for reagents and J. Goodhouse for assistance with confocal imaging. C.H. and G.dS. were supported by NIH Training Grants awarded to UCLA and the MSTP, respectively, and S.H.J. was supported as a Harold W. Dodds Fellow of the Princeton University Graduate programme. This work was supported by grants from the NIH (NS 31885-05) (G.W.) and the Stop Cancer Foundation (G.W.) and the NIH (HD 30707) (T.F.V.) and funds provided to the Department of Molecular Biology by the Rathmann Family Foundation.

Author information

Author notes

  1. Stuart H. Johnston

    Present address: Exelixis Inc., 170 Harbour Way, South San Francisco, California, 94083-0511, USA

  2. Thomas F. Vogt

    Present address: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA

Authors and Affiliations

  1. Department of Chemistry,

    Carol Hicks, Guy diSibio & Gerry Weinmaster

  2. Department of Neurobiology,

    Carol Hicks

  3. Department of Molecular Biology, Princeton University, Princeton, New Jersey, 08544, USA

    Stuart H. Johnston & Thomas F. Vogt

  4. Molecular Biology Institute, UCLA School of Medicine , Los Angeles, 90095-1737, California, USA

    Guy diSibio

  5. House Ear Institute, 2100 West 3rd Street, Los Angeles, California, 90057-1922, USA

    Andres Collazo

Authors
  1. Carol Hicks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stuart H. Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guy diSibio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andres Collazo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas F. Vogt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gerry Weinmaster
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Thomas F. Vogt or Gerry Weinmaster.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hicks, C., Johnston, S., diSibio, G. et al. Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nat Cell Biol 2, 515–520 (2000). https://doi.org/10.1038/35019553

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35019553

This article is cited by

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