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Gene Review

Nkx2-1  -  NK2 homeobox 1

Mus musculus

Synonyms: AV026640, Homeobox protein Nkx-2.1, Nkx-2.1, Nkx2.1, T/EBP, ...
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Disease relevance of Titf1


Psychiatry related information on Titf1

  • Transcriptional factors including Nkx2.1, HNF family forkhead homologues, GATA family zinc finger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, glucocorticoid and retinoic acid receptors mediate and integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination [3].

High impact information on Titf1


Chemical compound and disease context of Titf1

  • BACKGROUND/PURPOSE: The well-established Adriamycin rat model of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) complements recently described mouse genetic models in which loss of function mutations in foregut patterning genes, such as Nkx2.1 (Ttf 1), lead to OA/TOF [7].

Biological context of Titf1

  • Targeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, Titf1) in mice results in ablation of the pituitary [8].
  • Thus, in contrast to the null Titf1 mutation, the Titf1PM/PM mutant substantially restored lung morphogenesis [9].
  • We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice [10].
  • Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency [11].
  • The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1 [11].

Anatomical context of Titf1


Associations of Titf1 with chemical compounds


Physical interactions of Titf1


Regulatory relationships of Titf1

  • TTF-1 regulates expression of MK in the lung [19].
  • By contrast, as indicated by both loss- and gain-of-function analysis, Gsh2 expression in the medial ganglionic eminence after E10.5 may negatively regulate Nkx2.1 dependent specification of oligodendrocytes [20].
  • However, the remaining tissues reconstituted Gsc and Shh activity and expressed the ventral forebrain marker Nkx2 [21].
  • A model is also supported whereby alpha(7) is induced by the essential pulmonary transcription factor TTF-1 and suppressed by Egr-1 during pulmonary development [15].
  • 5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2 [22].

Other interactions of Titf1

  • In this study, we demonstrate synergistic transactivation by C/EBPalpha and Nkx2.1 in the regulation of the CCSP gene [23].
  • Furthermore, MK expression was not detected in lungs of TTF-1 null mice [19].
  • Early cardiac development might therefore be regulated by other genes, which may act either independently or in concert with Csx/Nkx2 [24].
  • Moreover, we show that Pax8 and TTF-1 cooperate in the activation of the thyroglobulin promoter and that additional thyroid-specific mechanism(s) are involved in such a cooperation [25].
  • Notably, in the prospective amygdala region where Shh expression persists in the Nkx2.1 mutant, the presence of plp/dm20 is unperturbed [26].

Analytical, diagnostic and therapeutic context of Titf1


  1. Hypothyroidism in thyroid transcription factor 1 haploinsufficiency is caused by reduced expression of the thyroid-stimulating hormone receptor. Moeller, L.C., Kimura, S., Kusakabe, T., Liao, X.H., Van Sande, J., Refetoff, S. Mol. Endocrinol. (2003) [Pubmed]
  2. Increased expression of thyroid transcription factor-1 (TTF-1) in respiratory epithelial cells inhibits alveolarization and causes pulmonary inflammation. Wert, S.E., Dey, C.R., Blair, P.A., Kimura, S., Whitsett, J.A. Dev. Biol. (2002) [Pubmed]
  3. The molecular basis of lung morphogenesis. Warburton, D., Schwarz, M., Tefft, D., Flores-Delgado, G., Anderson, K.D., Cardoso, W.V. Mech. Dev. (2000) [Pubmed]
  4. Follicular cells of the thyroid gland require Pax8 gene function. Mansouri, A., Chowdhury, K., Gruss, P. Nat. Genet. (1998) [Pubmed]
  5. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C.H., Ward, J.M., Gonzalez, F.J. Genes Dev. (1996) [Pubmed]
  6. Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2. Shiratori, H., Sakuma, R., Watanabe, M., Hashiguchi, H., Mochida, K., Sakai, Y., Nishino, J., Saijoh, Y., Whitman, M., Hamada, H. Mol. Cell (2001) [Pubmed]
  7. Dorsoventral patterning in oesophageal atresia with tracheo-oesophageal fistula: Evidence from a new mouse model. Ioannides, A.S., Chaudhry, B., Henderson, D.J., Spitz, L., Copp, A.J. J. Pediatr. Surg. (2002) [Pubmed]
  8. Formation of Rathke's pouch requires dual induction from the diencephalon. Takuma, N., Sheng, H.Z., Furuta, Y., Ward, J.M., Sharma, K., Hogan, B.L., Pfaff, S.L., Westphal, H., Kimura, S., Mahon, K.A. Development (1998) [Pubmed]
  9. TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression. DeFelice, M., Silberschmidt, D., DiLauro, R., Xu, Y., Wert, S.E., Weaver, T.E., Bachurski, C.J., Clark, J.C., Whitsett, J.A. J. Biol. Chem. (2003) [Pubmed]
  10. A mouse model demonstrates a multigenic origin of congenital hypothyroidism. Amendola, E., De Luca, P., Macchia, P.E., Terracciano, D., Rosica, A., Chiappetta, G., Kimura, S., Mansouri, A., Affuso, A., Arra, C., Macchia, V., Di Lauro, R., De Felice, M. Endocrinology (2005) [Pubmed]
  11. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. Pohlenz, J., Dumitrescu, A., Zundel, D., Martiné, U., Schönberger, W., Koo, E., Weiss, R.E., Cohen, R.N., Kimura, S., Refetoff, S. J. Clin. Invest. (2002) [Pubmed]
  12. Altered gene expression with abnormal patterning of the telencephalon in embryos of diabetic Albino Swiss mice. Liao, D.M., Ng, Y.K., Tay, S.S., Ling, E.A., Dheen, S.T. Diabetologia (2004) [Pubmed]
  13. Nuclear factor I/thyroid transcription factor 1 interactions modulate surfactant protein C transcription. Bachurski, C.J., Yang, G.H., Currier, T.A., Gronostajski, R.M., Hong, D. Mol. Cell. Biol. (2003) [Pubmed]
  14. Key developmental regulators change during hyperoxia-induced injury and recovery in adult mouse lung. Pogach, M.S., Cao, Y., Millien, G., Ramirez, M.I., Williams, M.C. J. Cell. Biochem. (2007) [Pubmed]
  15. Temporal-spatial expression and transcriptional regulation of alpha7 nicotinic acetylcholine receptor by thyroid transcription factor-1 and early growth response factor-1 during murine lung development. Reynolds, P.R., Hoidal, J.R. J. Biol. Chem. (2005) [Pubmed]
  16. TAZ interacts with TTF-1 and regulates expression of surfactant protein-C. Park, K.S., Whitsett, J.A., Di Palma, T., Hong, J.H., Yaffe, M.B., Zannini, M. J. Biol. Chem. (2004) [Pubmed]
  17. Thyroid-specific transcription factors control Hex promoter activity. Puppin, C., D'Elia, A.V., Pellizzari, L., Russo, D., Arturi, F., Presta, I., Filetti, S., Bogue, C.W., Denson, L.A., Damante, G. Nucleic Acids Res. (2003) [Pubmed]
  18. Regulation of mouse SP-B gene promoter by AP-1 family members. Sever-Chroneos, Z., Bachurski, C.J., Yan, C., Whitsett, J.A. Am. J. Physiol. (1999) [Pubmed]
  19. Thyroid transcription factor (TTF) -1 regulates the expression of midkine (MK) during lung morphogenesis. Reynolds, P.R., Mucenski, M.L., Whitsett, J.A. Dev. Dyn. (2003) [Pubmed]
  20. Combinatorial function of the homeodomain proteins Nkx2.1 and Gsh2 in ventral telencephalic patterning. Corbin, J.G., Rutlin, M., Gaiano, N., Fishell, G. Development (2003) [Pubmed]
  21. The morphogenetic role of midline mesendoderm and ectoderm in the development of the forebrain and the midbrain of the mouse embryo. Camus, A., Davidson, B.P., Billiards, S., Khoo, P., Rivera-Pérez, J.A., Wakamiya, M., Behringer, R.R., Tam, P.P. Development (2000) [Pubmed]
  22. PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5. Ganga, M., Espinoza, H.M., Cox, C.J., Morton, L., Hjalt, T.A., Lee, Y., Amendt, B.A. J. Biol. Chem. (2003) [Pubmed]
  23. Synergistic transactivation of the differentiation-dependent lung gene Clara cell secretory protein (secretoglobin 1a1) by the basic region leucine zipper factor CCAAT/enhancer-binding protein alpha and the homeodomain factor Nkx2.1/thyroid transcription factor-1. Cassel, T.N., Berg, T., Suske, G., Nord, M. J. Biol. Chem. (2002) [Pubmed]
  24. Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. Tanaka, M., Kasahara, H., Bartunkova, S., Schinke, M., Komuro, I., Inagaki, H., Lee, Y., Lyons, G.E., Izumo, S. Dev. Genet. (1998) [Pubmed]
  25. Pax8 has a key role in thyroid cell differentiation. Pasca di Magliano, M., Di Lauro, R., Zannini, M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  26. Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Nery, S., Wichterle, H., Fishell, G. Development (2001) [Pubmed]
  27. The WNT7b promoter is regulated by TTF-1, GATA6, and Foxa2 in lung epithelium. Weidenfeld, J., Shu, W., Zhang, L., Millar, S.E., Morrisey, E.E. J. Biol. Chem. (2002) [Pubmed]
  28. A model of pulmonary adenocarcinoma in transgenic mice expressing the simian virus 40 T antigen driven by the rat Calbindin-D9K (CaBP9K) promoter. Chailley-Heu, B., Rambaud, C., Barlier-Mur, A.M., Galateau-Salle, F., Perret, C., Capron, F., Lacaze-Masmonteil, T. J. Pathol. (2001) [Pubmed]
  29. Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation. Archavachotikul, K., Ciccone, T.J., Chinoy, M.R., Nielsen, H.C., Volpe, M.V. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  30. Side population cells and Bcrp1 expression in lung. Summer, R., Kotton, D.N., Sun, X., Ma, B., Fitzsimmons, K., Fine, A. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
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