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Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator

Abstract

In Drosophila, signalling by the protein Hedgehog (Hh) alters the activity of the transcription factor Cubitus interruptus (Ci) by inhibiting the proteolysis of full-length Ci (Ci-155) to its shortened Ci-75 form1,2. Ci-75 is found largely in the nucleus and isthought to be a transcriptional repressor1, whereas there is evidence3,4,5 to indicate that Ci-155 may be a transcriptional activator1,2,6. However, Ci-155 is detected only in the cytoplasm, where it is associated with the protein kinase Fused (Fu), with Suppressor of Fused (Su(fu)), and with the microtubule-binding protein Costal-2 (refs 1,7,8,9). It is not clear how Ci-155 might become a nuclear activator. We show here that mutations in Su ( fu) cause an increase in the expression of Hh-target genes in a dose-dependent manner while simultaneously reducing Ci-155 concentration by some mechanism other than proteolysis to Ci-75. Conversely, eliminating Fu kinase activity reduces Hh-target gene expression while increasing Ci-155 concentration. We propose that Fu kinase activity is required for Hh to stimulate the maturation of Ci-155 into a short-lived nuclear transcriptional activator and that Su(fu) opposes this maturation step through a stoichiometric interaction with Ci-155.

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Figure 1: Effects of Ci/Su(fu) ratio and Fu kinase activity on wing patterning.
Figure 2: Effects of Ci/Su(fu) ratio and Fu kinase activity on anterior expression ofEn and Ci-155.
Figure 3: Loss of Su ( fu) in embryos enhances ectopic wg expression and decreases Ci-155 levels resulting from PKA inhibition.
Figure 5: Effects of loss of Su ( fu) on the level of Ci-155 are epistatic to slimb and fu mutations.
Figure 4: Western blots of embryo and wing disc extracts.

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References

  1. Aza-Blanc, P., Ramirez-Weber, F.-A., Laget, M.-P., Schwarz, C. & Kornberg, T. B. Proteolysis that can be inhibited by Hedgehog directs Cubitus interruptus protein to the nucleus and changes its activity as a transcriptional regulator. Cell 89, 1043–1053 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Ingham, P. W. Transducing Hedgehog: the story so far. EMBO J. 17, 3505–2511 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Alexandre, C., Jacinto, A. & Ingham, P. W. Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the Cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. Genes Dev. 10, 2003–2013 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Von Ohlen, T. & Hooper, J. E. Hedgehog signaling regulates transcription through Gli/Ci binding sites in the wingless enhancer. Mech. Dev. 68, 149–156 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Forbes, A. J., Nakano, Y., Taylor, A. M. & Ingham, P. W. Genetic analysis of hedgehog signalling in the Drosophila embryo. Development(suppl.) 115–124 (1993).

  6. Akimaru, H. et al. Drosophila CBP is a co-activator of Cubitus interruptus in Hedgehog signalling. Nature 386, 735–738 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Monnier, V., Dussillol, F., Alves, G., Lamour-Isnard, C. & Plessis, A. Suppressor of fused links Fused and Cubitus interrupts on the Hedgehog signalling pathway. Curr. Biol. 8, 583–586 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Robbins, D. J. et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein Costal2. Cell 90, 225–234 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Sisson, J. C., Ho, K. S., Suyama, K. & Scott, M. P. Costal2, a novel kinesin-related protein in the hedgehog signaling pathway. Cell 90, 235–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Basler, K. & Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by Hedgehog protein. Nature 368, 208–214 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Blair, S. engrailed expression in the anterior lineage compartment of the developing wing blade of Drosophila. Development 115, 21–33 (1992).

    CAS  PubMed  Google Scholar 

  12. Strigini, M. & Cohen, S. M. AHedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124, 4697–4705 (1997).

    CAS  PubMed  Google Scholar 

  13. Sturtevant, M. A., Biehs, B., Marin, E. & Bier, E. The spalt gene links the A/P compartment boundary to a linear adult structure in the Drosophila wing. Development 124, 21–32 (1997).

    CAS  PubMed  Google Scholar 

  14. Hidalgo, A. Three distinct roles for the engrailed gene in Drosophila wing development. Curr. Biol. 4, 1087–1098 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Ingham, P. W. Localized hedgehog activity controls spatial limits of wingless transcription in the Drosophila embryo. Nature 366, 560–562 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Ohlmeyer, J. T. & Kalderon, D. Dual pathways for induction of wingless by protein kinase A and Hedgehog in Drosophila embryos. Genes Dev. 11, 2250–2258 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Motzny, C. K. & Holmgren, R. The Drosophila Cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways. Mech. Dev. 52, 137–150 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Busson, D., Limbourg-Bouchon, B., Mariol, M.-C., Preat, T. & Lamour-Isnard, C. Genetic analysis of viable and lethal fused mutants of Drosophila melanogaster. Roux Arch. Dev. Biol. 197, 221–230 (1988).

    Article  PubMed  Google Scholar 

  20. Préat, T. et al. Segmental polarity in Drosophila melanogaster: genetic dissection of fused in a Suppressor of fused background reveals interaction with costal-2. Genetics 135, 1047–1062 (1993).

    PubMed  PubMed Central  Google Scholar 

  21. Rodriguez, I. & Basler, K. Control of compartmental affinity boundaries by Hedgehog. Nature 389, 614–617 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Blair, S. S. & Ralston, A. Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior–posterior lineage restriction in the developing wing of Drosophila. Development 124, 4053–4063 (1997).

    CAS  PubMed  Google Scholar 

  23. Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M. & Hooper, J. E. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the Hedgehog signal. Cell 86, 221–232 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. van den Heuvel, M. & Ingham, P. W. smoothened encodes a receptor-like serpentine protein required for Hedgehog signalling. Nature 382, 547–551 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Chen, Y., Gallaher, N., Goodman, R. H. & Smolik, S. M. Protein kinase A directly regulates the activity and proteolysis of Cubitus Interruptus. Proc. Natl Acad. Sci. USA 95, 2349–2354 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mullor, J. L., Calleja, M., Capdevila, J. & Guerrero, I. Hedgehog activity, independent of Decapentaplegic, participates in wing disc patterning. Development 124, 1227–1237 (1997).

    CAS  PubMed  Google Scholar 

  27. Lane, M. E. & Kalderon, D. Genetic investigation of cAMP-dependent protein kinase function in Drosophila development. Genes Dev. 7, 1229–1243 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Therond, P. et al. Molecular organization and expression pattern of the segment polarity gene fused of Drosophila melanogaster. Mech. Dev. 44, 165–180 (1993).

    Article  Google Scholar 

  29. Préat, T. Characterization of Supressor of fused, a complete supressor of the fused segment polarity gene of Drosophila melanogaster. Genetics 132, 725–736 (1992).

    PubMed  PubMed Central  Google Scholar 

  30. Brunner, E., Peter, O., Schweizer, L. & Basler, K. pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila. Nature 385, 829–833 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Holmgren, P. Ingham, J. Jiang, T. Kornberg, C. Lamour-Isnard, N.Patel, N. Perrimon and A. Plessis for reagents; N. Baker, J. Erickson and J. Mohler for discussions, and the NIH for supporting this work.

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Correspondence to Daniel Kalderon.

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Ohlmeyer, J., Kalderon, D. Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator. Nature 396, 749–753 (1998). https://doi.org/10.1038/25533

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