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Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events

Abstract

The precise regulation of growth factor signalling is crucial to the molecular control of development in Drosophila. Post-translational modification of signalling molecules is one of the mechanisms that modulate developmental signalling specificity. We describe a new gene, fringe connection (frc), that encodes a nucleotide–sugar transporter that transfers UDP–glucuronic acid, UDP–N-acetylglucosamine and possibly UDP–xylose from the cytoplasm into the lumen of the endoplasmic reticulum/Golgi. Embryos with the frc mutation display defects in Wingless, Hedgehog and fibroblast growth factor signalling. Clonal analysis shows that fringe-dependent Notch signalling is disrupted in frc mutant tissue.

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Figure 1: Segment polarity phenotypes of frc mutant embryos.
Figure 2: Lateral migration of the mesoderm in frc mutant embryos.
Figure 3: Molecular and biochemical characterization of the frc gene.
Figure 4: The frc gene is required for HSPG biosynthesis.
Figure 5: Frc function during imaginal disc development.
Figure 6: The frc gene enhances the Notch Abruptex phenotype.

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References

  1. Binari, R. C. et al. Genetic evidence that heparin-like glycosaminoglycans are involved in wingless signaling. Development 124, 2623–2632 (1997).

    CAS  PubMed  Google Scholar 

  2. Haerry, T. E., Heslip, T. R., Marsh, J. L. & O'Connor, M. B. Defects in glucuronate biosynthesis disrupt Wingless signaling in Drosophila. Development 124, 3055–3064 (1997).

    CAS  PubMed  Google Scholar 

  3. Hacker, U., Lin, X. & Perrimon, N. The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide biosynthesis. Development 124, 3565–3573 (1997).

    CAS  PubMed  Google Scholar 

  4. Lin, X. & Perrimon, N. Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling. Nature 400, 281–284 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Tsuda, M. et al. The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila. Nature 400, 276–280 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Lin, X., Buff, E. M., Perrimon, N. & Michelson, A. M. Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development. Development 126, 3715–3723 (1999).

    CAS  PubMed  Google Scholar 

  7. The, I., Bellaiche, Y. & Perrimon, N. Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol. Cell 4, 633–639 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Bellaiche, Y., The, I. & Perrimon, N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394, 85–88 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Lind, T., Tufaro, F., McCormick, C., Lindahl, U. & Lidholt, K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J. Biol. Chem. 273, 26265–26268 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Perrimon, N. & Bernfield, M. Specificities of heparan sulfate proteoglycans in developmental processes. Nature 404, 725–729 (2000).

    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. Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Bruckner, K., Perez, L., Clausen, H. & Cohen, S. Glycosyltransferase activity of Fringe modulates Notch–Delta interactions. Nature 406, 411–415 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Klein, T. & Arias, A. M. Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development. Development 125, 2951–2962 (1998).

    CAS  PubMed  Google Scholar 

  16. Perrimon, N., Lanjuin, A., Arnold, C. & Noll, E. Zygotic lethal mutations with maternal effect phenotypes in Drosophila melanogaster. II. Loci on the second and third chromosomes identified by P-element-induced mutations. Genetics 144, 1681–1692 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Perrimon, N. The genetic basis of patterned baldness in Drosophila. Cell 76, 781–784 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. DiNardo, S., Sher, E., Heemskerk-Jongens, J., Kassis, J. A. & O'Farrell, P. H. Two-tiered regulation of spatially patterned engrailed gene expression during Drosophila embryogenesis. Nature 332, 604–609 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yoffe, K. B., Manoukian, A. S., Wilder, E. L., Brand, A. H. & Perrimon, N. Evidence for engrailed-independent wingless autoregulation in Drosophila. Dev. Biol. 170, 636–650 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Beiman, M., Shilo, B. Z. & Volk, T. Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages. Genes Dev. 10, 2993–3002 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Gisselbrecht, S., Skeath, J. B., Doe, C. Q. & Michelson, A. M. heartless encodes a fibroblast growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo. Genes Dev. 10, 3003–3017 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Herman, T. & Horvitz, H. R. Three proteins involved in Caenorhabditis elegans vulval invagination are similar to components of a glycosylation pathway. Proc. Natl Acad. Sci. USA 96, 974–979 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herman, T., Hartwieg, E. & Horvitz, H. R. sqv mutants of Caenorhabditis elegans are defective in vulval epithelial invagination. Proc. Natl Acad. Sci. USA 96, 968–973 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ma, D., Russell, D. G., Beverley, S. M. & Turco, S. J. Golgi GDP–mannose uptake requires Leishmania LPG2. A member of a eukaryotic family of putative nucleotide–sugar transporters. J. Biol. Chem. 272, 3799–3805 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Hong, K., Ma, D., Beverley, S. M. & Turco, S. J. The Leishmania GDP–mannose transporter is an autonomous, multi-specific, hexameric complex of LPG2 subunits. Biochemistry 39, 2013–2022 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Berninsone, P., Hwang, H. Y., Zemtseva, I., Horvitz, H. R. & Hirschberg, C. B. SQV-7, a protein involved in Caenorhabditis elegans epithelial invagination and early embryogenesis, transports UDP–glucuronic acid, UDP–N-acetylgalactosamine, and UDP–galactose. Proc. Natl Acad. Sci. USA 98, 3738–3743 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Abeijon, C., Mandon, E. C. & Hirschberg, C. B. Transporters of nucleotide sugars, nucleotide sulfate and ATP in the Golgi apparatus. Trends Biochem. Sci. 22, 203–207 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Khare, N. & Baumgartner, S. Dally-like protein, a new Drosophila glypican with expression overlapping with wingless. Mech. Dev. 99, 199–202 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Baeg, G. H., Lin, X., Khare, N., Baumgartner, S. & Perrimon, N. Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 128, 87–94 (2001).

    CAS  PubMed  Google Scholar 

  30. de Celis, J. F., Tyler, D. M., de Celis, J. & Bray, S. J. Notch signalling mediates segmentation of the Drosophila leg. Development 125, 4617–4626 (1998).

    CAS  PubMed  Google Scholar 

  31. Rauskolb, C. & Irvine, K. D. Notch-mediated segmentation and growth control of the Drosophila leg. Dev. Biol. 210, 339–350 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Kim, J., Irvine, K. D. & Carroll, S. B. Cell recognition, signal induction, and symmetrical gene activation at the dorsal–ventral boundary of the developing Drosophila wing. Cell 82, 795–802 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Foster, G. G. Negative complementation at the notch locus of Drosophila melanogaster. Genetics 81, 99–120 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Portin, P. Allelic negative complementation at the Abruptex locus of Drosophila melanogaster. Genetics 81, 121–133 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Munro, S. & Freeman, M. The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD. Curr. Biol. 10, 813–820 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. 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 

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

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. Spradling, A. C. et al. Gene disruptions using P transposable elements: an integral component of the Drosophila genome project. Proc. Natl Acad. Sci. USA 92, 10824–10830 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wilder, E. L. & Perrimon, N. Dual functions of wingless in the Drosophila leg imaginal disc. Development 121, 477–488 (1995).

    CAS  PubMed  Google Scholar 

  45. Ingham, P. W. & Fietz, M. J. Quantitative effects of hedgehog and decapentaplegic activity on the patterning of the Drosophila wing. Curr. Biol. 5, 432–440 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Ito, K., Awano, W., Suzuki, K., Hiromi, Y. & Yamamoto, D. The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. Development 124, 761–771 (1997).

    CAS  PubMed  Google Scholar 

  47. Duffy, J. B., Harrison, D. A. & Perrimon, N. Identifying loci required for follicular patterning using directed mosaics. Development 125, 2263–2271 (1998).

    CAS  PubMed  Google Scholar 

  48. Guo, Y. C. & Conrad, H. E. The disaccharide composition of heparins and heparan sulfates. Anal. Biochem. 176, 96–104 (1989).

    Article  CAS  PubMed  Google Scholar 

  49. Goud, B., Salminen, A., Walworth, N. C. & Novick, P. J. A GTP-binding protein required for secretion rapidly associates with secretory vesicles and the plasma membrane in yeast. Cell 53, 753–768 (1988).

    Article  CAS  PubMed  Google Scholar 

  50. Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195 (2000).

    Article  PubMed  Google Scholar 

  51. Goto, S. et al. UDP–sugar transporter implicated in glycosylation and processing of Notch. Nature Cell Biol. 3, 816–822 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Zeidler, B. Stronach and K. Brückner for comments on the manuscript, and C. Hirschberg, C. Abeijon, P. Berninsone, S. Cherry, K. Nybakken and I. The for helpful discussions. Special thanks to K. Irvine, S. Artananis-Tsakonas and J. de Celis for stocks, S. Baumgartner for the Dally-like antibody, H. Agaisse for help with the northern analysis, and C. Hartmann for performing the plasmid rescue experiments. N.P. is an Investigator of the Howard Hughes Medical Institute. This work was supported by NIH Grant AI31078 (S.J.T. and S.M.B.) and GM61110 (N.P.), as well as HFSP (N.P.).

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Correspondence to Norbert Perrimon.

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Selva, E., Hong, K., Baeg, GH. et al. Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events. Nat Cell Biol 3, 809–815 (2001). https://doi.org/10.1038/ncb0901-809

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