• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Jun 2, 1997; 16(11): 3185–3197.
PMCID: PMC1169936

TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation.


Expression of thyroglobulin (Tg) and thyroperoxidase (TPO) genes in thyroid follicular cells occurs in the mouse at embryonic day (E)14.5. Two transcription factors, TTF-1 and Pax-8, have been implicated in transcriptional activation of Tg and TPO, even though the onset of their expression is at E9.5, suggesting that additional events are necessary for transcriptional activation of Tg and TPO genes. We report in this paper the cloning of TTF-2, a DNA binding protein that recognizes sites on both Tg and TPO promoters. TTF-2 is a new forkhead domain-containing protein whose expression is restricted to the endodermal lining of the foregut and to the ectoderm that will give rise to the anterior pituitary. TTF-2 shows transient expression in the developing thyroid and anterior pituitary. In the thyroid, TTF-2 expression is down-regulated just before the onset of Tg and TPO gene expression, suggesting that this transcription factor plays the role in development of a negative controller of thyroid-specific gene expression.

Full Text

The Full Text of this article is available as a PDF (1.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ambesi-Impiombato FS, Coon HG. Thyroid cells in culture. Int Rev Cytol Suppl. 1979;(10):163–172. [PubMed]
  • Aza-Blanc P, Di Lauro R, Santisteban P. Identification of a cis-regulatory element and a thyroid-specific nuclear factor mediating the hormonal regulation of rat thyroid peroxidase promoter activity. Mol Endocrinol. 1993 Oct;7(10):1297–1306. [PubMed]
  • Bohinski RJ, Di Lauro R, Whitsett JA. The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis. Mol Cell Biol. 1994 Sep;14(9):5671–5681. [PMC free article] [PubMed]
  • Briata P, Van De Werken R, Airoldi I, Ilengo C, Di Blas E, Boncinelli E, Corte G. Transcriptional repression by the human homeobox protein EVX1 in transfected mammalian cells. J Biol Chem. 1995 Nov 17;270(46):27695–27701. [PubMed]
  • Catron KM, Zhang H, Marshall SC, Inostroza JA, Wilson JM, Abate C. Transcriptional repression by Msx-1 does not require homeodomain DNA-binding sites. Mol Cell Biol. 1995 Feb;15(2):861–871. [PMC free article] [PubMed]
  • Chidambaram A, Dean M. Genetics of the nevoid basal cell carcinoma syndrome. Adv Cancer Res. 1996;70:49–61. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. [PMC free article] [PubMed]
  • Civitareale D, Lonigro R, Sinclair AJ, 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. [PMC free article] [PubMed]
  • Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature. 1993 Jul 29;364(6436):412–420. [PubMed]
  • Clevidence DE, Overdier DG, Tao W, Qian X, Pani L, Lai E, Costa RH. Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3948–3952. [PMC free article] [PubMed]
  • Damante G, Di Lauro R. Thyroid-specific gene expression. Biochim Biophys Acta. 1994 Aug 2;1218(3):255–266. [PubMed]
  • De Felice M, Damante G, Zannini M, Francis-Lang H, Di Lauro R. Redundant domains contribute to the transcriptional activity of the thyroid transcription factor 1. J Biol Chem. 1995 Nov 3;270(44):26649–26656. [PubMed]
  • De Simone V, Cortese R. Transcriptional regulation of liver-specific gene expression. Curr Opin Cell Biol. 1991 Dec;3(6):960–965. [PubMed]
  • de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. [PMC free article] [PubMed]
  • Elkabes S, Loh YP, Nieburgs A, Wray S. Prenatal ontogenesis of pro-opiomelanocortin in the mouse central nervous system and pituitary gland: an in situ hybridization and immunocytochemical study. Brain Res Dev Brain Res. 1989 Mar 1;46(1):85–95. [PubMed]
  • Falvo JV, Thanos D, Maniatis T. Reversal of intrinsic DNA bends in the IFN beta gene enhancer by transcription factors and the architectural protein HMG I(Y). Cell. 1995 Dec 29;83(7):1101–1111. [PubMed]
  • Pierrou S, Hellqvist M, Samuelsson L, Enerbäck S, Carlsson P. Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. EMBO J. 1994 Oct 17;13(20):5002–5012. [PMC free article] [PubMed]
  • Giese K, Kingsley C, Kirshner JR, Grosschedl R. Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev. 1995 Apr 15;9(8):995–1008. [PubMed]
  • Poleev A, Fickenscher H, Mundlos S, Winterpacht A, Zabel B, Fidler A, Gruss P, Plachov D. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Development. 1992 Nov;116(3):611–623. [PubMed]
  • Gstaiger M, Knoepfel L, Georgiev O, Schaffner W, Hovens CM. A B-cell coactivator of octamer-binding transcription factors. Nature. 1995 Jan 26;373(6512):360–362. [PubMed]
  • Rowe LB, Nadeau JH, Turner R, Frankel WN, Letts VA, Eppig JT, Ko MS, Thurston SJ, Birkenmeier EH. Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm Genome. 1994 May;5(5):253–274. [PubMed]
  • Santisteban P, Acebrón A, Polycarpou-Schwarz M, Di Lauro R. Insulin and insulin-like growth factor I regulate a thyroid-specific nuclear protein that binds to the thyroglobulin promoter. Mol Endocrinol. 1992 Aug;6(8):1310–1317. [PubMed]
  • Sato K, Di Lauro R. Hepatocyte nuclear factor 3beta participates in the transcriptional regulation of the thyroperoxidase promoter. Biochem Biophys Res Commun. 1996 Mar 7;220(1):86–93. [PubMed]
  • Holloway JM, Szeto DP, Scully KM, Glass CK, Rosenfeld MG. Pit-1 binding to specific DNA sites as a monomer or dimer determines gene-specific use of a tyrosine-dependent synergy domain. Genes Dev. 1995 Aug 15;9(16):1992–2006. [PubMed]
  • Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994 Oct 13;371(6498):606–609. [PubMed]
  • Kaestner KH, Lee KH, Schlöndorff J, Hiemisch H, Monaghan AP, Schütz G. Six members of the mouse forkhead gene family are developmentally regulated. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7628–7631. [PMC free article] [PubMed]
  • Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996 Jan 1;10(1):60–69. [PubMed]
  • Thanos D, Maniatis T. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell. 1995 Dec 29;83(7):1091–1100. [PubMed]
  • Lamonerie T, Tremblay JJ, Lanctôt C, Therrien M, Gauthier Y, Drouin J. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev. 1996 May 15;10(10):1284–1295. [PubMed]
  • 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. [PubMed]
  • Zannini M, Francis-Lang H, Plachov D, Di Lauro R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol Cell Biol. 1992 Sep;12(9):4230–4241. [PMC free article] [PubMed]
  • Lin SC, Li S, Drolet DW, Rosenfeld MG. Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development. 1994 Mar;120(3):515–522. [PubMed]
  • Luo Y, Fujii H, Gerster T, Roeder RG. A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell. 1992 Oct 16;71(2):231–241. [PubMed]
  • McPherson CE, Shim EY, Friedman DS, Zaret KS. An active tissue-specific enhancer and bound transcription factors existing in a precisely positioned nucleosomal array. Cell. 1993 Oct 22;75(2):387–398. [PubMed]
  • McPherson CE, Horowitz R, Woodcock CL, Jiang C, Zaret KS. Nucleosome positioning properties of the albumin transcriptional enhancer. Nucleic Acids Res. 1996 Feb 1;24(3):397–404. [PMC free article] [PubMed]
  • Mitchell PJ, Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. [PubMed]
  • Mock BA, Stoye J, Spence J, Jackson I, Eppig JT, Fiedorek FT, Jr, Neumann PE. Encyclopedia of the mouse genome V. Mouse chromosome 4. Mamm Genome. 1996;6(Spec No):S73–S96. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    PubChem Compound links
  • Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...