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Gene Review

Nkx2-5  -  NK2 homeobox 5

Mus musculus

Synonyms: Cardiac-specific homeobox, Csx, Homeobox protein CSX, Homeobox protein NK-2 homolog E, Homeobox protein Nkx-2.5, ...
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Disease relevance of Nkx2-5


High impact information on Nkx2-5


Chemical compound and disease context of Nkx2-5


Biological context of Nkx2-5

  • We describe a cardiac enhancer, located about 9 kilobases upstream of the Nkx2-5 gene, that fully recapitulates the expression pattern of the endogenous gene in cardiogenic precursor cells from the onset of cardiac lineage specification and throughout the linear and looping heart tube [12].
  • The homeobox gene Nkx2-5 is the earliest known marker of the cardiac lineage in vertebrate embryos [12].
  • Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes [13].
  • These results reveal a novel GATA-dependent mechanism for activation of Nkx2-5 transcription in the developing heart and indicate that regulation of Nkx2-5 is controlled in a modular manner, with multiple regulatory regions responding to distinct transcriptional networks in different compartments of the developing heart [12].
  • To test for an early cardiogenic function for Nkx2-5 and to examine whether cardiogenic mechanisms are conserved, we introduced the mouse Nkx2-5 gene and various mutant and chimeric derivatives into the Drosophila germline, and tested for their ability to rescue the tin mutant phenotype [14].

Anatomical context of Nkx2-5

  • Co-transfection assays using a dominant negative mutant Nkx2-5 construct with CARP promoter-luciferase reporter constructs in cardiac myocytes confirms that Nkx2-5 either directly or indirectly regulates carp at the transcriptional level [13].
  • While tin itself strongly rescued both heart and visceral mesoderm, Nkx2-5 rescued only visceral mesoderm [14].
  • In addition to the heart, Nkx2-5 is transiently expressed in the developing pharynx, thyroid and stomach [12].
  • Complete Tbx20 knockdown resulted in defects in heart formation, including hypoplasia of the outflow tract and right ventricle, which derive from the anterior heart field (AHF), and decreased expression of Nkx2-5 and Mef2c, transcription factors required for AHF formation [15].
  • We observed the absence of myogenic alpha-actins, SM22alpha, and myocardin expression and the failure to form beating cardiac myocytes in aggregated SRF null embryonic stem cells, whereas the appearance of transcription factors Nkx2-5 and GATA4 were unaffected [16].

Associations of Nkx2-5 with chemical compounds


Physical interactions of Nkx2-5


Regulatory relationships of Nkx2-5

  • Transient-transfection assays indicate that Csx can activate ANF reporter gene expression to the same extent that GATA4 does in a DNA binding site-dependent manner [25].
  • Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis [26].
  • In addition, the nuclear translocation of NFATc1 in the endocardial endothelial cells is inhibited in the Nkx2-5-/- embryos [27].
  • Complex cardiac Nkx2-5 gene expression activated by noggin-sensitive enhancers followed by chamber-specific modules [28].
  • During heart formation, Lbh is expressed as early as Nkx2.5 and dHand in the bilateral heart primordia, with the highest levels in the anterior promyocardium [29].

Other interactions of Nkx2-5

  • Interestingly, in mutant embryos homozygous for Nkx2.6, Nkx2.5 expression extended to the lateral side of the pharynx, suggesting a compensatory function of Nkx2.5 in the mutant pharyngeal pouches [30].
  • Expression of Nkx2.6 overlaps that of Nkx2.5 in the pharynx and heart and that of Nkx2.3 in the pharynx [30].
  • The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer [22].
  • Mice heterozygous for mutant alleles of Nkx2.5 and dHAND were viable [31].
  • Early cardiac development might therefore be regulated by other genes, which may act either independently or in concert with Csx/Nkx2 [32].

Analytical, diagnostic and therapeutic context of Nkx2-5


  1. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Pashmforoush, M., Lu, J.T., Chen, H., Amand, T.S., Kondo, R., Pradervand, S., Evans, S.M., Clark, B., Feramisco, J.R., Giles, W., Ho, S.Y., Benson, D.W., Silberbach, M., Shou, W., Chien, K.R. Cell (2004) [Pubmed]
  2. Expression of Nkx2-5-GFP bacterial artificial chromosome transgenic mice closely resembles endogenous Nkx2-5 gene activity. Chi, X., Zhang, S.X., Yu, W., DeMayo, F.J., Rosenberg, S.M., Schwartz, R.J. Genesis (2003) [Pubmed]
  3. Haploinsufficiency of the cardiac transcription factor Nkx2-5 variably affects the expression of putative target genes. Jay, P.Y., Rozhitskaya, O., Tarnavski, O., Sherwood, M.C., Dorfman, A.L., Lu, Y., Ueyama, T., Izumo, S. FASEB J. (2005) [Pubmed]
  4. The Transcriptional Coactivator CAMTA2 Stimulates Cardiac Growth by Opposing Class II Histone Deacetylases. Song, K., Backs, J., McAnally, J., Qi, X., Gerard, R.D., Richardson, J.A., Hill, J.A., Bassel-Duby, R., Olson, E.N. Cell (2006) [Pubmed]
  5. p204 is required for the differentiation of P19 murine embryonal carcinoma cells to beating cardiac myocytes: its expression is activated by the cardiac Gata4, Nkx2.5, and Tbx5 proteins. Ding, B., Liu, C.J., Huang, Y., Hickey, R.P., Yu, J., Kong, W., Lengyel, P. J. Biol. Chem. (2006) [Pubmed]
  6. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Prall, O.W., Menon, M.K., Solloway, M.J., Watanabe, Y., Zaffran, S., Bajolle, F., Biben, C., McBride, J.J., Robertson, B.R., Chaulet, H., Stennard, F.A., Wise, N., Schaft, D., Wolstein, O., Furtado, M.B., Shiratori, H., Chien, K.R., Hamada, H., Black, B.L., Saga, Y., Robertson, E.J., Buckingham, M.E., Harvey, R.P. Cell (2007) [Pubmed]
  7. Hop is an unusual homeobox gene that modulates cardiac development. Chen, F., Kook, H., Milewski, R., Gitler, A.D., Lu, M.M., Li, J., Nazarian, R., Schnepp, R., Jen, K., Biben, C., Runke, G., Mackay, J.P., Novotny, J., Schwartz, R.J., Harvey, R.P., Mullins, M.C., Epstein, J.A. Cell (2002) [Pubmed]
  8. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Habets, P.E., Moorman, A.F., Clout, D.E., van Roon, M.A., Lingbeek, M., van Lohuizen, M., Campione, M., Christoffels, V.M. Genes Dev. (2002) [Pubmed]
  9. Homeodomain factor Nkx2-5 controls left/right asymmetric expression of bHLH gene eHand during murine heart development. Biben, C., Harvey, R.P. Genes Dev. (1997) [Pubmed]
  10. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Lyons, I., Parsons, L.M., Hartley, L., Li, R., Andrews, J.E., Robb, L., Harvey, R.P. Genes Dev. (1995) [Pubmed]
  11. Molecular cloning and expression of HRLRRP, a novel heart-restricted leucine-rich repeat protein. Nakane, T., Satoh, T., Inada, Y., Nakayama, J., Itoh, F., Chiba, S. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  12. Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. Lien, C.L., Wu, C., Mercer, B., Webb, R., Richardson, J.A., Olson, E.N. Development (1999) [Pubmed]
  13. CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. Zou, Y., Evans, S., Chen, J., Kuo, H.C., Harvey, R.P., Chien, K.R. Development (1997) [Pubmed]
  14. Divergent roles for NK-2 class homeobox genes in cardiogenesis in flies and mice. Ranganayakulu, G., Elliott, D.A., Harvey, R.P., Olson, E.N. Development (1998) [Pubmed]
  15. Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development. Takeuchi, J.K., Mileikovskaia, M., Koshiba-Takeuchi, K., Heidt, A.B., Mori, A.D., Arruda, E.P., Gertsenstein, M., Georges, R., Davidson, L., Mo, R., Hui, C.C., Henkelman, R.M., Nemer, M., Black, B.L., Nagy, A., Bruneau, B.G. Development (2005) [Pubmed]
  16. Conditional mutagenesis of the murine serum response factor gene blocks cardiogenesis and the transcription of downstream gene targets. Niu, Z., Yu, W., Zhang, S.X., Barron, M., Belaguli, N.S., Schneider, M.D., Parmacek, M., Nordheim, A., Schwartz, R.J. J. Biol. Chem. (2005) [Pubmed]
  17. An HF-1a/HF-1b/MEF-2 combinatorial element confers cardiac ventricular specificity and established an anterior-posterior gradient of expression. Ross, R.S., Navankasattusas, S., Harvey, R.P., Chien, K.R. Development (1996) [Pubmed]
  18. Cardiomyocytes can be generated from marrow stromal cells in vitro. Makino, S., Fukuda, K., Miyoshi, S., Konishi, F., Kodama, H., Pan, J., Sano, M., Takahashi, T., Hori, S., Abe, H., Hata, J., Umezawa, A., Ogawa, S. J. Clin. Invest. (1999) [Pubmed]
  19. Opioid peptide gene expression primes cardiogenesis in embryonal pluripotent stem cells. Ventura, C., Maioli, M. Circ. Res. (2000) [Pubmed]
  20. Jumonji represses atrial natriuretic factor gene expression by inhibiting transcriptional activities of cardiac transcription factors. Kim, T.G., Chen, J., Sadoshima, J., Lee, Y. Mol. Cell. Biol. (2004) [Pubmed]
  21. Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes. Kawamura, T., Ono, K., Morimoto, T., Wada, H., Hirai, M., Hidaka, K., Morisaki, T., Heike, T., Nakahata, T., Kita, T., Hasegawa, K. J. Biol. Chem. (2005) [Pubmed]
  22. The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer. Brown, C.O., Chi, X., Garcia-Gras, E., Shirai, M., Feng, X.H., Schwartz, R.J. J. Biol. Chem. (2004) [Pubmed]
  23. Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Nowotschin, S., Liao, J., Gage, P.J., Epstein, J.A., Campione, M., Morrow, B.E. Development (2006) [Pubmed]
  24. Direct activation of a GATA6 cardiac enhancer by Nkx2.5: evidence for a reinforcing regulatory network of Nkx2.5 and GATA transcription factors in the developing heart. Molkentin, J.D., Antos, C., Mercer, B., Taigen, T., Miano, J.M., Olson, E.N. Dev. Biol. (2000) [Pubmed]
  25. The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Lee, Y., Shioi, T., Kasahara, H., Jobe, S.M., Wiese, R.J., Markham, B.E., Izumo, S. Mol. Cell. Biol. (1998) [Pubmed]
  26. Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis. Ueyama, T., Kasahara, H., Ishiwata, T., Nie, Q., Izumo, S. Mol. Cell. Biol. (2003) [Pubmed]
  27. Dysregulation of connexins and inactivation of NFATc1 in the cardiovascular system of Nkx2-5 null mutants. Dupays, L., Jarry-Guichard, T., Mazurais, D., Calmels, T., Izumo, S., Gros, D., Théveniau-Ruissy, M. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  28. Complex cardiac Nkx2-5 gene expression activated by noggin-sensitive enhancers followed by chamber-specific modules. Chi, X., Chatterjee, P.K., Wilson, W., Zhang, S.X., Demayo, F.J., Schwartz, R.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  29. Identification and characterization of Lbh, a novel conserved nuclear protein expressed during early limb and heart development. Briegel, K.J., Joyner, A.L. Dev. Biol. (2001) [Pubmed]
  30. Phenotypic characterization of the murine Nkx2.6 homeobox gene by gene targeting. Tanaka, M., Yamasaki, N., Izumo, S. Mol. Cell. Biol. (2000) [Pubmed]
  31. The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Yamagishi, H., Yamagishi, C., Nakagawa, O., Harvey, R.P., Olson, E.N., Srivastava, D. Dev. Biol. (2001) [Pubmed]
  32. 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]
  33. Regulation of the tinman homologues in Xenopus embryos. Sparrow, D.B., Cai, C., Kotecha, S., Latinkic, B., Cooper, B., Towers, N., Evans, S.M., Mohun, T.J. Dev. Biol. (2000) [Pubmed]
  34. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Lints, T.J., Parsons, L.M., Hartley, L., Lyons, I., Harvey, R.P. Development (1993) [Pubmed]
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