Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene.[1][2][3]
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][3]
Interactions
NKX2-5 has been shown to interact with GATA4[4][5][6] and TBX5.[4][7] 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.
References
- ^ 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". Genomics 27 (1): 204–6. doi:10.1006/geno.1995.1027. PMID 7665173.
- ^ Turbay D, Wechsler SB, Blanchard KM, Izumo S (January 1997). "Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx". Mol Med 2 (1): 86–96. PMC 2230031. PMID 8900537.
- ^ a b "Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)".
- ^ a b Garg, Vidu; Kathiriya Irfan S, Barnes Robert, Schluterman Marie K, King Isabelle N, Butler Cheryl A, Rothrock Caryn R, Eapen Reenu S, Hirayama-Yamada Kayoko, Joo Kunitaka, Matsuoka Rumiko, Cohen Jonathan C, Srivastava Deepak (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature (England) 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.
- ^ Durocher, D; Charron F; Warren R; Schwartz R J; Nemer M (September 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". EMBO J. (ENGLAND) 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. ISSN 0261-4189. PMC 1170200. PMID 9312027.
- ^ 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. ISSN 0021-9258. PMID 10948187.
- ^ Hiroi, Y; Kudoh S; Monzen K; Ikeda Y; Yazaki Y; Nagai R; Komuro I (July 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nat. Genet. (United States) 28 (3): 276–80. doi:10.1038/90123. ISSN 1061-4036. PMID 11431700.
Further reading
- Harvey RP, Lai D, Elliott D et al. (2003). "Homeodomain factor Nkx2-5 in heart development and disease.". Cold Spring Harb. Symp. Quant. Biol. 67: 107–14. doi:10.1101/sqb.2002.67.107. PMID 12858530.
- Chen CY, Schwartz RJ (1996). "Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription.". Mol. Cell. Biol. 16 (11): 6372–84. PMC 231639. PMID 8887666.
- Durocher D, Charron F, Warren R et al. (1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors.". EMBO J. 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC 1170200. PMID 9312027.
- Schott JJ, Benson DW, Basson CT et al. (1998). "Congenital heart disease caused by mutations in the transcription factor NKX2-5.". Science 281 (5373): 108–11. doi:10.1126/science.281.5373.108. PMID 9651244.
- 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. PMID 9748262.
- Kasahara H, Izumo S (1999). "Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5.". Mol. Cell. Biol. 19 (1): 526–36. PMC 83910. PMID 9858576.
- Benson DW, Silberbach GM, Kavanaugh-McHugh A et al. (2000). "Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.". J. Clin. Invest. 104 (11): 1567–73. doi:10.1172/JCI8154. PMC 409866. PMID 10587520.
- Kasahara H, Lee B, Schott JJ et al. (2000). "Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease.". J. Clin. Invest. 106 (2): 299–308. doi:10.1172/JCI9860. PMC 314312. PMID 10903346.
- 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. PMID 10948187.
- 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. PMID 11431700.
- Goldmuntz E, Geiger E, Benson DW (2001). "NKX2.5 mutations in patients with tetralogy of fallot.". Circulation 104 (21): 2565–8. doi:10.1161/hc4601.098427. PMID 11714651.
- 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. PMID 11889119.
- Habets PE, Moorman AF, Clout DE et al. (2002). "Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation.". Genes Dev. 16 (10): 1234–46. doi:10.1101/gad.222902. PMC 186286. PMID 12023302.
- 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. PMID 12074273.
- Shirai M, Osugi T, Koga H et al. (2002). "The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis.". J. Clin. Invest. 110 (2): 177–84. doi:10.1172/JCI14839. PMC 151044. PMID 12122109.
- Watanabe Y, Benson DW, Yano S et al. (2002). "Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD.". J. Med. Genet. 39 (11): 807–11. doi:10.1136/jmg.39.11.807. PMC 1735007. PMID 12414819.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Fan C, Liu M, Wang Q (2003). "Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome.". J. Biol. Chem. 278 (10): 8780–5. doi:10.1074/jbc.M208120200. PMC 1579789. PMID 12499378.
External links
- NKX2-5 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
|