- Letter
- Published:
Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator
Naturevolume 396, pages749–753 (1998)Cite this article
1207Accesses
Abstract
InDrosophila, 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 inSu (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.
This is a preview of subscription content,access via your institution
Access options
Subscription info for Japanese customers
We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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.Cell89, 1043–1053 (1997).
Ingham, P. W. Transducing Hedgehog: the story so far.EMBO J.17, 3505–2511 (1998).
Alexandre, C., Jacinto, A. & Ingham, P. W. Transcriptional activation ofhedgehog target genes inDrosophila is mediated directly by theCubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins.Genes Dev.10, 2003–2013 (1996).
Von Ohlen, T. & Hooper, J. E. Hedgehog signaling regulates transcription through Gli/Ci binding sites in thewingless enhancer.Mech. Dev.68, 149–156 (1997).
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).
Akimaru, H.et al.Drosophila CBP is a co-activator of Cubitus interruptus in Hedgehog signalling.Nature386, 735–738 (1997).
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).
Robbins, D. J.et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein Costal2.Cell90, 225–234 (1997).
Sisson, J. C., Ho, K. S., Suyama, K. & Scott, M. P. Costal2, a novel kinesin-related protein in the hedgehog signaling pathway.Cell90, 235–245 (1997).
Basler, K. & Struhl, G. Compartment boundaries and the control ofDrosophila limb pattern by Hedgehog protein.Nature368, 208–214 (1994).
Blair, S.engrailed expression in the anterior lineage compartment of the developing wing blade ofDrosophila.Development115, 21–33 (1992).
Strigini, M. & Cohen, S. M. AHedgehog activity gradient contributes to AP axial patterning of the Drosophila wing.Development124, 4697–4705 (1997).
Sturtevant, M. A., Biehs, B., Marin, E. & Bier, E. Thespalt gene links the A/P compartment boundary to a linear adult structure in theDrosophila wing.Development124, 21–32 (1997).
Hidalgo, A. Three distinct roles for theengrailed gene inDrosophila wing development.Curr. Biol.4, 1087–1098 (1994).
Ingham, P. W. Localizedhedgehog activity controls spatial limits ofwingless transcription in theDrosophila embryo.Nature366, 560–562 (1993).
Ohlmeyer, J. T. & Kalderon, D. Dual pathways for induction ofwingless by protein kinase A and Hedgehog inDrosophila embryos.Genes Dev.11, 2250–2258 (1997).
Motzny, C. K. & Holmgren, R. TheDrosophila Cubitus interruptus protein and its role in thewingless andhedgehog signal transduction pathways.Mech. Dev.52, 137–150 (1995).
Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.Nature391, 493–496 (1998).
Busson, D., Limbourg-Bouchon, B., Mariol, M.-C., Preat, T. & Lamour-Isnard, C. Genetic analysis of viable and lethalfused mutants ofDrosophila melanogaster.Roux Arch. Dev. Biol.197, 221–230 (1988).
Préat, T.et al. Segmental polarity inDrosophila melanogaster: genetic dissection offused in aSuppressor of fused background reveals interaction withcostal-2.Genetics135, 1047–1062 (1993).
Rodriguez, I. & Basler, K. Control of compartmental affinity boundaries by Hedgehog.Nature389, 614–617 (1997).
Blair, S. S. & Ralston, A. Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior–posterior lineage restriction in the developing wing ofDrosophila.Development124, 4053–4063 (1997).
Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M. & Hooper, J. E. TheDrosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the Hedgehog signal.Cell86, 221–232 (1996).
van den Heuvel, M. & Ingham, P. W.smoothened encodes a receptor-like serpentine protein required for Hedgehog signalling.Nature382, 547–551 (1996).
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. USA95, 2349–2354 (1998).
Mullor, J. L., Calleja, M., Capdevila, J. & Guerrero, I. Hedgehog activity, independent of Decapentaplegic, participates in wing disc patterning.Development124, 1227–1237 (1997).
Lane, M. E. & Kalderon, D. Genetic investigation of cAMP-dependent protein kinase function inDrosophila development.Genes Dev.7, 1229–1243 (1993).
Therond, P.et al. Molecular organization and expression pattern of the segment polarity genefused ofDrosophila melanogaster.Mech. Dev.44, 165–180 (1993).
Préat, T. Characterization ofSupressor of fused, a complete supressor of thefused segment polarity gene ofDrosophila melanogaster.Genetics132, 725–736 (1992).
Brunner, E., Peter, O., Schweizer, L. & Basler, K.pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal inDrosophila.Nature385, 829–833 (1997).
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.
Author information
Authors and Affiliations
Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue, New York, 10027, New York, USA
Johanna Talavera Ohlmeyer & Daniel Kalderon
- Johanna Talavera Ohlmeyer
You can also search for this author inPubMed Google Scholar
- Daniel Kalderon
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toDaniel Kalderon.
Rights and permissions
About this article
Cite this article
Ohlmeyer, J., Kalderon, D. Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator.Nature396, 749–753 (1998). https://doi.org/10.1038/25533
Received:
Accepted:
Issue Date:
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
