Abstract
The TGF-β (transforming growth factor-β)-related signalling proteins, including Decapentaplegic (Dpp) in Drosophila and bone morphogenic proteins and activin in vertebrates, affect the growth and patterning of a great variety of structures. However, the mechanisms by which these ligands regulate gene expression are not understood. Activation of complexes of type I with type II receptors results in the phosphorylation and nuclear localization of members of the SMAD protein family1,2,3,4,5,6,7,8,9, which are thought to act as co-activators of transcription, perhaps in conjunction with sequence-specific cofactors10. Here we show that the amino-terminal domain of the Drosophila Mothers against dpp protein (Mad), a mediator of Dpp signalling11,12,13,14, possesses a sequence-specific DNA-binding activity that becomes apparent when carboxy-terminal residues are removed. Mad binds to and is required for the activation of an enhancer within the vestigial wing-patterning gene in cells across the entire developing wing blade. Mad also binds to Dpp-response elements in other genes. These results suggest that Dpp signalling regulates gene expression by activating Mad binding to target gene enhancers.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Graff, J. M., Bansal, A. & Melton, D. A. Xenopus Mad proteins transduce distinct subsets of signals for the TGFβ superfamily. Cell 85, 479–487 (1996).
Hoodless, P. A. et al. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 85, 489–500 (1996).
Liu, F. et al. Ahuman Mad protein acting as a BMP-regulated transcriptional activator. Nature 381, 622–623 (1996).
Eppert, K. et al. MADR2 maps to 18q21 and encodes a TGF β-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543–552 (1996).
Zhang, Y., Feng, X.-H., Wu, R.-Y. & Derynck, R. Receptor-associated Mad homologues synergize as effectors of the TGF-β response. Nature 383, 168–172 (1996).
Lagna, G., Hata, A., Hemmati-Brivnlou, A. & Massagué, J. Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383, 832–836 (1996).
Savage, C. et al. C. elegans genes sma-2, sma-3, and sma-4 genes define a conserved family of TGF-β pathway components. Proc. Natl Acad. Sci. USA 93, 790–794 (1996).
Macias-Silva, M. et al. MADR2 is a substrate of the TGF-β receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87, 1215–1224 (1996).
Derynck, R. & Zhang, Y. Intracellular signalling: The Mad way to do it. Curr. Biol. 6, 1226–1229 (1996).
Chen, X., Rubock, M. J. & Whitman, M. Atranscriptional partner for MAD proteins in TGF-β signalling. Nature 383, 691–696 (1996).
Raftery, L., Twombly, V., Wharton, K. & Gelbart, W. Genetic screens to identify elements of the decapentaplegic pathway in Drosophila. Genetics 139, 241–254 (1995).
Sekelsky, J., Newfeld, S., Raftery, L., Chartoff, E. & Gelbart, W. Genetic characterization and cloning of Mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347–1358 (1995).
Newfeld, S. J., Chartoff, E. H., Graff, J. M., Melton, D. A. & Gelbart, W. M. Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGF-β responsive cells. Development 122, 2099–2108 (1996).
Wiersdorff, V., Lecuit, T., Cohen, S. M. & Mlodzik, M. Mad acts downstream of Dpp receptors, revealing a differential requirement for dpp signaling in initiation and propagation of morphogenesis in the Drosophila eye. Development 122, 2153–2162 (1996).
Blair, S. Compartments and appendage development in Drosophila. BioEssays 17, 229–309 (1995).
Basler, K. & Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368, 208–214 (1994).
Tabata, T. & Kornberg, T. Hedgehog is a signalling protein with a key role in patterning Drosophila imaginal discs. Cell 76, 89–102 (1994).
Zecca, M., Basler, K. & Struhl, G. Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development 121, 2265–2278 (1995).
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).
Posakony, L., Raftery, L. & Gelbart, W. Wing formation in Drosophila melanogaster requires decapentaplegic gene function along the anterior–posterior compartment boundary. Mech. Dev. 33, 69–82 (1991).
Capdevilla, J. & Guerrero, I. Targeted expression of the signalling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings. EMBO J. 13, 4459–4468 (1994).
Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a Dpp morphogen gradient. Cell 85, 357–368 (1996).
Lecuit, T. et al. Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing. Nature 381, 387–393 (1996).
Kim, J. et al. Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature 382, 133–138 (1996).
de Celis, J. F., Bario, R. & Kafatos, F. C. Agene complex acting downstream of dpp in Drosophila wing morphogenesis. Nature 381, 421–424 (1996).
Grimm, S. & Pflugfelder, G. O. Control of the gene optomotor-blind in Drosophila wing development by decapentaplegic and wingless. Science 271, 1601–1604 (1996).
Chouinard, S. & Kaufman, T. C. Control of expression of the homeotic labial (lab) locus of Drosophila melanogaster: evidence for both positive and negative autogenous regulation. Development 113, 1267–1280 (1991).
Tremml, G. & Bienz, M. Induction of labial expression in the Drosophila endoderm: response elements for dpp signalling and for autoregulation. Development 116, 447–456 (1992).
Thuringer, F., Cohen, S. M. & Bienz, M. Dissection of an indirect autoregulatory response of a homeotic Drosophila gene. EMBO J. 12, 2419–2430 (1993).
Eresh, S., Riese, J., Jackson, D. B., Bohmann, D. & Bienz, M. ACREB-binding site as a target for decapentaplegic signalling during Drosophila endoderm induction. EMBO J. 16, 2014–2022 (1997).
Ausubel, F. M. et al. (eds) Current Protocols in Molecular Biology supplement 28, pp. 16.6.1–16.7.7 (Wiley, New York, (1994)).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, J., Johnson, K., Chen, H. et al. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 388, 304–308 (1997). https://doi.org/10.1038/40906
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/40906
This article is cited by
-
The effects of maternal care on the developmental transcriptome and metatranscriptome of a wild bee
Communications Biology (2023)
-
Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc
Nature Communications (2021)
-
PfSMAD1/5 Can Interact with PfSMAD4 to Inhibit PfMSX to Regulate Shell Biomineralization in Pinctada fucata martensii
Marine Biotechnology (2020)
-
SMAD3 and SMAD4 have a more dominant role than SMAD2 in TGFβ-induced chondrogenic differentiation of bone marrow-derived mesenchymal stem cells
Scientific Reports (2017)
-
Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors
Nature Communications (2017)
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.