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. 1997 Apr 15;16(8):2032–2042. doi: 10.1093/emboj/16.8.2032

A model for extradenticle function as a switch that changes HOX proteins from repressors to activators.

J Pinsonneault 1, B Florence 1, H Vaessin 1, W McGinnis 1
PMCID: PMC1169806  PMID: 9155029

Abstract

The Drosophila EXD protein and its mammalian counterparts, the PBX proteins, have been proposed to function in HOX target selectivity. Here we show that exd function is required for the autoactivation phase of Dfd expression in the posterior head. Mutations that change the affinity of a small autoactivation element for EXD protein result in corresponding changes in the element's embryonic activity. Our data suggest that the EXD and DFD proteins directly activate this element in maxillary cells without cooperatively binding to a specialized heterodimer binding site. Based on the types of homeotic transformations and changes in gene expression observed in exd mutant embryos, we propose a new model for EXD/PBX action in which these proteins are required for HOX protein transcriptional activation functions, but dispensable for HOX transcriptional repression functions. Although the selection of a specific target gene by a HOX protein versus another may be explained in some cases by the selective modulation of HOX binding specificity by EXD, we favor the idea that EXD interacts in a more general sense with most HOX proteins to switch them into a state where they are capable of transcriptional activation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Affolter M., Percival-Smith A., Müller M., Leupin W., Gehring W. J. DNA binding properties of the purified Antennapedia homeodomain. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4093–4097. doi: 10.1073/pnas.87.11.4093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akam M. The molecular basis for metameric pattern in the Drosophila embryo. Development. 1987 Sep;101(1):1–22. [PubMed] [Google Scholar]
  3. Bergson C., McGinnis W. An autoregulatory enhancer element of the Drosophila homeotic gene Deformed. EMBO J. 1990 Dec;9(13):4287–4297. doi: 10.1002/j.1460-2075.1990.tb07877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. CURR J. F. Synovial osteochondromatosis; two uncommon examples. Br Med J. 1949 Nov 5;2(4635):1020-2, illust; pl. doi: 10.1136/bmj.2.4635.1020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Capovilla M., Brandt M., Botas J. Direct regulation of decapentaplegic by Ultrabithorax and its role in Drosophila midgut morphogenesis. Cell. 1994 Feb 11;76(3):461–475. doi: 10.1016/0092-8674(94)90111-2. [DOI] [PubMed] [Google Scholar]
  6. Chan S. K., Jaffe L., Capovilla M., Botas J., Mann R. S. The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein. Cell. 1994 Aug 26;78(4):603–615. doi: 10.1016/0092-8674(94)90525-8. [DOI] [PubMed] [Google Scholar]
  7. Chan S. K., Pöpperl H., Krumlauf R., Mann R. S. An extradenticle-induced conformational change in a HOX protein overcomes an inhibitory function of the conserved hexapeptide motif. EMBO J. 1996 May 15;15(10):2476–2487. [PMC free article] [PubMed] [Google Scholar]
  8. Chang C. P., Shen W. F., Rozenfeld S., Lawrence H. J., Largman C., Cleary M. L. Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes Dev. 1995 Mar 15;9(6):663–674. doi: 10.1101/gad.9.6.663. [DOI] [PubMed] [Google Scholar]
  9. 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. 1991 Dec;113(4):1267–1280. doi: 10.1242/dev.113.4.1267. [DOI] [PubMed] [Google Scholar]
  10. González-Crespo S., Morata G. Control of Drosophila adult pattern by extradenticle. Development. 1995 Jul;121(7):2117–2125. doi: 10.1242/dev.121.7.2117. [DOI] [PubMed] [Google Scholar]
  11. González-Reyes A., Morata G. The developmental effect of overexpressing a Ubx product in Drosophila embryos is dependent on its interactions with other homeotic products. Cell. 1990 May 4;61(3):515–522. doi: 10.1016/0092-8674(90)90533-k. [DOI] [PubMed] [Google Scholar]
  12. Gross C. T., McGinnis W. DEAF-1, a novel protein that binds an essential region in a Deformed response element. EMBO J. 1996 Apr 15;15(8):1961–1970. [PMC free article] [PubMed] [Google Scholar]
  13. Harding K. W., Gellon G., McGinnis N., McGinnis W. A screen for modifiers of Deformed function in Drosophila. Genetics. 1995 Aug;140(4):1339–1352. doi: 10.1093/genetics/140.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jack T., McGinnis W. Establishment of the Deformed expression stripe requires the combinatorial action of coordinate, gap and pair-rule proteins. EMBO J. 1990 Apr;9(4):1187–1198. doi: 10.1002/j.1460-2075.1990.tb08226.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kennison J. A. Transcriptional activation of Drosophila homeotic genes from distant regulatory elements. Trends Genet. 1993 Mar;9(3):75–79. doi: 10.1016/0168-9525(93)90227-9. [DOI] [PubMed] [Google Scholar]
  16. Knoepfler P. S., Kamps M. P. The pentapeptide motif of Hox proteins is required for cooperative DNA binding with Pbx1, physically contacts Pbx1, and enhances DNA binding by Pbx1. Mol Cell Biol. 1995 Oct;15(10):5811–5819. doi: 10.1128/mcb.15.10.5811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lou L., Bergson C., McGinnis W. Deformed expression in the Drosophila central nervous system is controlled by an autoactivated intronic enhancer. Nucleic Acids Res. 1995 Sep 11;23(17):3481–3487. doi: 10.1093/nar/23.17.3481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Macías A., Morata G. Functional hierarchy and phenotypic suppression among Drosophila homeotic genes: the labial and empty spiracles genes. EMBO J. 1996 Jan 15;15(2):334–343. [PMC free article] [PubMed] [Google Scholar]
  19. Mann R. S. The specificity of homeotic gene function. Bioessays. 1995 Oct;17(10):855–863. doi: 10.1002/bies.950171007. [DOI] [PubMed] [Google Scholar]
  20. McGinnis W., Jack T., Chadwick R., Regulski M., Bergson C., McGinnis N., Kuziora M. A. Establishment and maintenance of position-specific expression of the Drosophila homeotic selector gene Deformed. Adv Genet. 1990;27:363–402. doi: 10.1016/s0065-2660(08)60030-9. [DOI] [PubMed] [Google Scholar]
  21. McGinnis W., Krumlauf R. Homeobox genes and axial patterning. Cell. 1992 Jan 24;68(2):283–302. doi: 10.1016/0092-8674(92)90471-n. [DOI] [PubMed] [Google Scholar]
  22. Neuteboom S. T., Peltenburg L. T., van Dijk M. A., Murre C. The hexapeptide LFPWMR in Hoxb-8 is required for cooperative DNA binding with Pbx1 and Pbx2 proteins. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9166–9170. doi: 10.1073/pnas.92.20.9166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. O'Neill J. W., Bier E. Double-label in situ hybridization using biotin and digoxigenin-tagged RNA probes. Biotechniques. 1994 Nov;17(5):870, 874-5. [PubMed] [Google Scholar]
  24. Peifer M., Wieschaus E. Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity. Genes Dev. 1990 Jul;4(7):1209–1223. doi: 10.1101/gad.4.7.1209. [DOI] [PubMed] [Google Scholar]
  25. Peltenburg L. T., Murre C. Engrailed and Hox homeodomain proteins contain a related Pbx interaction motif that recognizes a common structure present in Pbx. EMBO J. 1996 Jul 1;15(13):3385–3393. [PMC free article] [PubMed] [Google Scholar]
  26. Rauskolb C., Peifer M., Wieschaus E. extradenticle, a regulator of homeotic gene activity, is a homolog of the homeobox-containing human proto-oncogene pbx1. Cell. 1993 Sep 24;74(6):1101–1112. doi: 10.1016/0092-8674(93)90731-5. [DOI] [PubMed] [Google Scholar]
  27. Rauskolb C., Smith K. M., Peifer M., Wieschaus E. extradenticle determines segmental identities throughout Drosophila development. Development. 1995 Nov;121(11):3663–3673. doi: 10.1242/dev.121.11.3663. [DOI] [PubMed] [Google Scholar]
  28. Tremml G., Bienz M. Induction of labial expression in the Drosophila endoderm: response elements for dpp signalling and for autoregulation. Development. 1992 Oct;116(2):447–456. doi: 10.1242/dev.116.2.447. [DOI] [PubMed] [Google Scholar]
  29. Zeng C., Pinsonneault J., Gellon G., McGinnis N., McGinnis W. Deformed protein binding sites and cofactor binding sites are required for the function of a small segment-specific regulatory element in Drosophila embryos. EMBO J. 1994 May 15;13(10):2362–2377. doi: 10.1002/j.1460-2075.1994.tb06520.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. van Dijk M. A., Murre C. extradenticle raises the DNA binding specificity of homeotic selector gene products. Cell. 1994 Aug 26;78(4):617–624. doi: 10.1016/0092-8674(94)90526-6. [DOI] [PubMed] [Google Scholar]
  31. van Dijk M. A., Peltenburg L. T., Murre C. Hox gene products modulate the DNA binding activity of Pbx1 and Pbx2. Mech Dev. 1995 Jul;52(1):99–108. doi: 10.1016/0925-4773(95)00394-g. [DOI] [PubMed] [Google Scholar]

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