Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1994 Jul 15;13(14):3339–3347. doi: 10.1002/j.1460-2075.1994.tb06636.x

The thyroid transcription factor-1 gene is a candidate target for regulation by Hox proteins.

S Guazzi 1, R Lonigro 1, L Pintonello 1, E Boncinelli 1, R Di Lauro 1, F Mavilio 1
PMCID: PMC395231  PMID: 7913891

Abstract

Vertebrate Hox homeobox genes are transcription factors which regulate antero-posterior axial identity in embryogenesis, presumably through activation and/or repression of downstream target genes. Some of these targets were reported to code for molecules involved in cell-cell interactions, whereas no relationship has yet been demonstrated between Hox genes and other transcription factors involved in determining and/or maintaining tissue specificity. The thyroid transcription factor-1 (TTF-1) is a homeodomain-containing protein required for expression of thyroid-specific genes. A 862 bp 5' genomic fragment of the rat TTF-1 gene, conferring thyroid-specific expression to a reporter gene, was sufficient to mediate transactivation by the human HOXB3 gene in co-transfection assay in both NIH3T3 or HeLa cells. HOXB3 is expressed in early mammalian embryogenesis in the anterior neuroectoderm, branchial arches and their derivatives, including the area of the thyroid primordia and thyroid gland. Transcription of the TTF-1 promoter is induced only by HOXB3, while its paralogous gene HOXD3 or other Hox genes expressed more posteriorly (HOXA4, HOXD4, HOXC5, HOXC6, HOXC8 and Hoxd-8) have no effect. Transactivation by HOXB3 is mediated by two binding sites containing an ATTA core located at -100 and +30 from the transcription start site. DNase I footprinting experiments show that the two sites bind HOXB3 protein synthesized in both Escherichia coli and eukaryotic cells, as well as nuclear factor(s) present in protein extracts obtained from mouse embryonic tissues which express group 3 Hox genes and TTF-1. Some of the DNA-protein complexes formed by the embryonic extracts are indistinguishable from those generated by HOXB3.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
3341

Images in this article

3340Image
on p.3340
3341Image
on p.3341
3341Image
on p.3341
3342Image
on p.3342
3342Image
on p.3342
3343Image
on p.3343
3344Image
on p.3344
3344Image
on p.3344
3344Image
on p.3344

Selected References

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

  1. Acampora D., D'Esposito M., Faiella A., Pannese M., Migliaccio E., Morelli F., Stornaiuolo A., Nigro V., Simeone A., Boncinelli E. The human HOX gene family. Nucleic Acids Res. 1989 Dec 25;17(24):10385–10402. doi: 10.1093/nar/17.24.10385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Affolter M., Schier A., Gehring W. J. Homeodomain proteins and the regulation of gene expression. Curr Opin Cell Biol. 1990 Jun;2(3):485–495. doi: 10.1016/0955-0674(90)90132-x. [DOI] [PubMed] [Google Scholar]
  3. Appel B., Sakonju S. Cell-type-specific mechanisms of transcriptional repression by the homeotic gene products UBX and ABD-A in Drosophila embryos. EMBO J. 1993 Mar;12(3):1099–1109. doi: 10.1002/j.1460-2075.1993.tb05751.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arcioni L., Simeone A., Guazzi S., Zappavigna V., Boncinelli E., Mavilio F. The upstream region of the human homeobox gene HOX3D is a target for regulation by retinoic acid and HOX homeoproteins. EMBO J. 1992 Jan;11(1):265–277. doi: 10.1002/j.1460-2075.1992.tb05049.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonnerot C., Rocancourt D., Briand P., Grimber G., Nicolas J. F. A beta-galactosidase hybrid protein targeted to nuclei as a marker for developmental studies. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6795–6799. doi: 10.1073/pnas.84.19.6795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Buettner R., Yim S. O., Hong Y. S., Boncinelli E., Tainsky M. A. Alteration of homeobox gene expression by N-ras transformation of PA-1 human teratocarcinoma cells. Mol Cell Biol. 1991 Jul;11(7):3573–3583. doi: 10.1128/mcb.11.7.3573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Chisaka O., Capecchi M. R. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature. 1991 Apr 11;350(6318):473–479. doi: 10.1038/350473a0. [DOI] [PubMed] [Google Scholar]
  9. Civitareale D., Lonigro R., Sinclair A. J., Di Lauro R. A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J. 1989 Sep;8(9):2537–2542. doi: 10.1002/j.1460-2075.1989.tb08391.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Condie B. G., Capecchi M. R. Mice homozygous for a targeted disruption of Hoxd-3 (Hox-4.1) exhibit anterior transformations of the first and second cervical vertebrae, the atlas and the axis. Development. 1993 Nov;119(3):579–595. doi: 10.1242/dev.119.3.579. [DOI] [PubMed] [Google Scholar]
  11. Damante G., Di Lauro R. Several regions of Antennapedia and thyroid transcription factor 1 homeodomains contribute to DNA binding specificity. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5388–5392. doi: 10.1073/pnas.88.12.5388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Desplan C., Theis J., O'Farrell P. H. The sequence specificity of homeodomain-DNA interaction. Cell. 1988 Sep 23;54(7):1081–1090. doi: 10.1016/0092-8674(88)90123-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Duboule D. The vertebrate limb: a model system to study the Hox/HOM gene network during development and evolution. Bioessays. 1992 Jun;14(6):375–384. doi: 10.1002/bies.950140606. [DOI] [PubMed] [Google Scholar]
  15. Francis-Lang H., Price M., Polycarpou-Schwarz M., Di Lauro R. Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. Mol Cell Biol. 1992 Feb;12(2):576–588. doi: 10.1128/mcb.12.2.576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gaunt S. J. Homoeobox gene Hox-1.5 expression in mouse embryos: earliest detection by in situ hybridization is during gastrulation. Development. 1987 Sep;101(1):51–60. [PubMed] [Google Scholar]
  17. Gehring W. J. Homeo boxes in the study of development. Science. 1987 Jun 5;236(4806):1245–1252. doi: 10.1126/science.2884726. [DOI] [PubMed] [Google Scholar]
  18. Gehring W. J., Müller M., Affolter M., Percival-Smith A., Billeter M., Qian Y. Q., Otting G., Wüthrich K. The structure of the homeodomain and its functional implications. Trends Genet. 1990 Oct;6(10):323–329. doi: 10.1016/0168-9525(90)90253-3. [DOI] [PubMed] [Google Scholar]
  19. Gould A. P., Brookman J. J., Strutt D. I., White R. A. Targets of homeotic gene control in Drosophila. Nature. 1990 Nov 22;348(6299):308–312. doi: 10.1038/348308a0. [DOI] [PubMed] [Google Scholar]
  20. Gould A. P., White R. A. Connectin, a target of homeotic gene control in Drosophila. Development. 1992 Dec;116(4):1163–1174. doi: 10.1242/dev.116.4.1163. [DOI] [PubMed] [Google Scholar]
  21. Green S., Issemann I., Sheer E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucleic Acids Res. 1988 Jan 11;16(1):369–369. doi: 10.1093/nar/16.1.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gruss P., Kessel M. Axial specification in higher vertebrates. Curr Opin Genet Dev. 1991 Aug;1(2):204–210. doi: 10.1016/s0959-437x(05)80071-1. [DOI] [PubMed] [Google Scholar]
  23. Guazzi S., Price M., De Felice M., Damante G., Mattei M. G., Di Lauro R. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J. 1990 Nov;9(11):3631–3639. doi: 10.1002/j.1460-2075.1990.tb07574.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hayashi S., Scott M. P. What determines the specificity of action of Drosophila homeodomain proteins? Cell. 1990 Nov 30;63(5):883–894. doi: 10.1016/0092-8674(90)90492-w. [DOI] [PubMed] [Google Scholar]
  25. Hinz U., Wolk A., Renkawitz-Pohl R. Ultrabithorax is a regulator of beta 3 tubulin expression in the Drosophila visceral mesoderm. Development. 1992 Nov;116(3):543–554. doi: 10.1242/dev.116.3.543. [DOI] [PubMed] [Google Scholar]
  26. Hoey T., Levine M. Divergent homeo box proteins recognize similar DNA sequences in Drosophila. Nature. 1988 Apr 28;332(6167):858–861. doi: 10.1038/332858a0. [DOI] [PubMed] [Google Scholar]
  27. Hunt P., Gulisano M., Cook M., Sham M. H., Faiella A., Wilkinson D., Boncinelli E., Krumlauf R. A distinct Hox code for the branchial region of the vertebrate head. Nature. 1991 Oct 31;353(6347):861–864. doi: 10.1038/353861a0. [DOI] [PubMed] [Google Scholar]
  28. Hunt P., Krumlauf R. Deciphering the Hox code: clues to patterning branchial regions of the head. Cell. 1991 Sep 20;66(6):1075–1078. doi: 10.1016/0092-8674(91)90029-x. [DOI] [PubMed] [Google Scholar]
  29. Hunt P., Wilkinson D., Krumlauf R. Patterning the vertebrate head: murine Hox 2 genes mark distinct subpopulations of premigratory and migrating cranial neural crest. Development. 1991 May;112(1):43–50. doi: 10.1242/dev.112.1.43. [DOI] [PubMed] [Google Scholar]
  30. Jaynes J. B., O'Farrell P. H. Activation and repression of transcription by homoeodomain-containing proteins that bind a common site. Nature. 1988 Dec 22;336(6201):744–749. doi: 10.1038/336744a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jones F. S., Holst B. D., Minowa O., De Robertis E. M., Edelman G. M. Binding and transcriptional activation of the promoter for the neural cell adhesion molecule by HoxC6 (Hox-3.3). Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6557–6561. doi: 10.1073/pnas.90.14.6557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jones F. S., Prediger E. A., Bittner D. A., De Robertis E. M., Edelman G. M. Cell adhesion molecules as targets for Hox genes: neural cell adhesion molecule promoter activity is modulated by cotransfection with Hox-2.5 and -2.4. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2086–2090. doi: 10.1073/pnas.89.6.2086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kessel M., Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991 Oct 4;67(1):89–104. doi: 10.1016/0092-8674(91)90574-i. [DOI] [PubMed] [Google Scholar]
  34. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Krasnow M. A., Saffman E. E., Kornfeld K., Hogness D. S. Transcriptional activation and repression by Ultrabithorax proteins in cultured Drosophila cells. Cell. 1989 Jun 16;57(6):1031–1043. doi: 10.1016/0092-8674(89)90341-3. [DOI] [PubMed] [Google Scholar]
  36. Krumlauf R. Hox genes and pattern formation in the branchial region of the vertebrate head. Trends Genet. 1993 Apr;9(4):106–112. doi: 10.1016/0168-9525(93)90203-t. [DOI] [PubMed] [Google Scholar]
  37. Lai E., Prezioso V. R., Tao W. F., Chen W. S., Darnell J. E., Jr Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Genes Dev. 1991 Mar;5(3):416–427. doi: 10.1101/gad.5.3.416. [DOI] [PubMed] [Google Scholar]
  38. Lazzaro D., Price M., de Felice M., Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development. 1991 Dec;113(4):1093–1104. doi: 10.1242/dev.113.4.1093. [DOI] [PubMed] [Google Scholar]
  39. Mavilio F. Regulation of vertebrate homeobox-containing genes by morphogens. Eur J Biochem. 1993 Mar 1;212(2):273–288. doi: 10.1111/j.1432-1033.1993.tb17660.x. [DOI] [PubMed] [Google Scholar]
  40. Mavilio F., Simeone A., Giampaolo A., Faiella A., Zappavigna V., Acampora D., Poiana G., Russo G., Peschle C., Boncinelli E. Differential and stage-related expression in embryonic tissues of a new human homoeobox gene. Nature. 1986 Dec 18;324(6098):664–668. doi: 10.1038/324664a0. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. Pöpperl H., Featherstone M. S. An autoregulatory element of the murine Hox-4.2 gene. EMBO J. 1992 Oct;11(10):3673–3680. doi: 10.1002/j.1460-2075.1992.tb05452.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schubert F. R., Nieselt-Struwe K., Gruss P. The Antennapedia-type homeobox genes have evolved from three precursors separated early in metazoan evolution. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):143–147. doi: 10.1073/pnas.90.1.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sham M. H., Hunt P., Nonchev S., Papalopulu N., Graham A., Boncinelli E., Krumlauf R. Analysis of the murine Hox-2.7 gene: conserved alternative transcripts with differential distributions in the nervous system and the potential for shared regulatory regions. EMBO J. 1992 May;11(5):1825–1836. doi: 10.1002/j.1460-2075.1992.tb05234.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Studier F. W., Rosenberg A. H., Dunn J. J., Dubendorff J. W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 1990;185:60–89. doi: 10.1016/0076-6879(90)85008-c. [DOI] [PubMed] [Google Scholar]
  46. Thali M., Müller M. M., DeLorenzi M., Matthias P., Bienz M. Drosophila homoeotic genes encode transcriptional activators similar to mammalian OTF-2. Nature. 1988 Dec 8;336(6199):598–601. doi: 10.1038/336598a0. [DOI] [PubMed] [Google Scholar]
  47. Tomotsune D., Shoji H., Wakamatsu Y., Kondoh H., Takahashi N. A mouse homologue of the Drosophila tumour-suppressor gene l(2)gl controlled by Hox-C8 in vivo. Nature. 1993 Sep 2;365(6441):69–72. doi: 10.1038/365069a0. [DOI] [PubMed] [Google Scholar]
  48. Wagner-Bernholz J. T., Wilson C., Gibson G., Schuh R., Gehring W. J. Identification of target genes of the homeotic gene Antennapedia by enhancer detection. Genes Dev. 1991 Dec;5(12B):2467–2480. doi: 10.1101/gad.5.12b.2467. [DOI] [PubMed] [Google Scholar]
  49. Weigel D., Seifert E., Reuter D., Jäckle H. Regulatory elements controlling expression of the Drosophila homeotic gene fork head. EMBO J. 1990 Apr;9(4):1199–1207. doi: 10.1002/j.1460-2075.1990.tb08227.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zappavigna V., Renucci A., Izpisúa-Belmonte J. C., Urier G., Peschle C., Duboule D. HOX4 genes encode transcription factors with potential auto- and cross-regulatory capacities. EMBO J. 1991 Dec;10(13):4177–4187. doi: 10.1002/j.1460-2075.1991.tb04996.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zappavigna V., Sartori D., Mavilio F. Specificity of HOX protein function depends on DNA-protein and protein-protein interactions, both mediated by the homeo domain. Genes Dev. 1994 Mar 15;8(6):732–744. doi: 10.1101/gad.8.6.732. [DOI] [PubMed] [Google Scholar]
  52. Zhao J. J., Lazzarini R. A., Pick L. The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene. Genes Dev. 1993 Mar;7(3):343–354. doi: 10.1101/gad.7.3.343. [DOI] [PubMed] [Google Scholar]
  53. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES