Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development (Shiojima et al., 1995). It has been demonstrated that a Drosophila homeobox-containing gene called 'tinman' is expressed in the developing dorsal vessel and in the equivalent of the vertebrate heart. Mutations in tinman result in loss of heart formation in the embryo, suggesting that tinman is essential for Drosophila heart formation. Furthermore, abundant expression of Csx, the presumptive mouse homolog of tinman, is observed only in the heart from the time of cardiac differentiation. CSX, the human homolog of murine Csx, has a homeodomain sequence identical to that of Csx and is expressed only in the heart, again suggesting that CSX plays an important role in human heart formation.[supplied by OMIM]
NKX2-5 has been shown to interact with GATA4 and TBX5. NKX 2.5 is a transcription factor that regulates heart development in humans. NKX2.5 works along with MEF2, HAND1, and HAND2 transcription factors to direct heart looping during early heart development. NKX2.5 in vertebrates is equivalent to the ‘tinman’ gene in Drosophila and directly activates the MEF2 gene to control cardiomyocyte differentiation. NKX2.5 operates in a positive feedback loop with GATA transcription factors to regulate cardiomyocyte formation. NKX2.5 influences HAND1 and HAND2 transcription factors that control the essential asymmetrical development of the heart’s ventricles. Gene mutations of NKX2.5 lead to heart looping defects, conduction defects, and atrial septal defects in the developing heart. Scientists developed a gene knockout model of NKX2.5 in mice and found that the number of myocytes that develop into conduction cells depends on the amount of NKX2.5 influence. Therefore, lack of NKX2.5 leads to reduced function of the atrioventricular (AV) node. Since the AV node electrically connects the atrial and ventricular chambers of the heart to control conductance, defects of the AV node would lead to congenital heart disease.
^Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, Nagai R, Yazaki Y (October 1995). "Assignment of cardiac homeobox gene CSX to human chromosome 5q34". Genomics27 (1): 204–6. doi:10.1006/geno.1995.1027. PMID7665173.
^Zhu, W; Shiojima I; Hiroi Y; Zou Y; Akazawa H; Mizukami M; Toko H; Yazaki Y; Nagai R; Komuro I (November 2000). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". J. Biol. Chem. (UNITED STATES) 275 (45): 35291–6. doi:10.1074/jbc.M000525200. ISSN0021-9258. PMID10948187.
Kim YH, Choi CY, Lee SJ, et al. (1998). "Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors.". J. Biol. Chem.273 (40): 25875–9. doi:10.1074/jbc.273.40.25875. PMID9748262.
Zhu W, Shiojima I, Hiroi Y, et al. (2001). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease.". J. Biol. Chem.275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID10948187.
Hiroi Y, Kudoh S, Monzen K, et al. (2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation.". Nat. Genet.28 (3): 276–80. doi:10.1038/90123. PMID11431700.
Toko H, Zhu W, Takimoto E, et al. (2002). "Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart.". J. Biol. Chem.277 (27): 24735–43. doi:10.1074/jbc.M107669200. PMID11889119.
Ikeda Y, Hiroi Y, Hosoda T, et al. (2002). "Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease.". Circ. J.66 (6): 561–3. doi:10.1253/circj.66.561. PMID12074273.