Wikipedia

Homeobox protein Nkx-2.5

Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2-5 gene.[5][6][7]

NKX2-5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNKX2-5, CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E, NKX4-1, VSD3, NK2 homeobox 5
External IDsOMIM: 600584; MGI: 97350; HomoloGene: 3230; GeneCards: NKX2-5; OMA:NKX2-5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1482

18091

Ensembl

ENSG00000183072

ENSMUSG00000015579

UniProt

P52952

P42582

RefSeq (mRNA)

NM_004387
NM_001166175
NM_001166176

NM_008700

RefSeq (protein)

NP_001159647
NP_001159648
NP_004378

NP_032726

Location (UCSC)Chr 5: 173.23 – 173.24 MbChr 17: 27.06 – 27.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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.[7] In humans, proper NKX2-5 expression is essential for the development of atrial, ventricular, and conotruncal septation, atrioventricular (AV) valve formation, and maintenance of AV conduction. Mutations in expression are associated with congenital heart disease (CHD) and related ailments. Patients with NKX2-5 mutations commonly present AV conduction block and atrial septal defects (ASD). Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. The NKX2-5 transcription factor may help myocytes endure cytotoxic stress, however further exploration in this field is required.[8]

NK-2 homeobox genes are a family of genes that encode for numerous transcription factors that go on to aid in the development of many structures including the thyroid, colon, and heart.[9][10][11] Of the NK-2 genes, NKX2-5 transcription factor is mostly involved in cardiac development and defects with this gene can lead to congenital heart defects including, but not limited to atrial septal defects.[12] NKX2-5 is expressed in precursor cardiac cells and this expression is necessary in order to lead to proper cardiac development.[13] In NKX2-5 gene knock out mice, subjects were found to have induced congenital heart defects by leading to differentially expressed genes.[14] In the case of loss of function of NKX2-5, test subjects developed increased heart rate and decreased variability in heart rate.[15] This discovery indicates that NKX2-5 is necessary for proper cardiac formatting as well as proper cardiac function after formatting. NKX2-5 has also been shown to bind to the promoter of FGF-16 and regulate its expression. This finding suggests that NKX2-5 is implicated in cardiac injury via cytotoxic effects.[16]

Interactions

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During embryogenesis, NKX2-5 is expressed in early cardiac mesoderm cells throughout the left ventricle and atrial chambers. In early cardiogenesis, cardiac precursor cells from the cardiac crescent congregate along the ventral midline of the developing embryo and form the linear heart tube. In Nkx2-5 knock out mice, cardiac development halts at the linear heart tube stage and looping morphogenesis disrupted.

NKX2-5 has been shown to interact with GATA4[17][18][19] and TBX5.[17][20] NKX2-5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans.[21] NKX2-5 is dependent upon the JAK-STAT pathway[22] and 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. The gene has been shown to play a role in the heart's conduction system, postnatally.[23] NKX2-5 is also involved in the intrinsic mechanisms that decide ventricle and atrial cellular fate. During ventricular chamber formation, NKX2-5 and NKX2-7 are required to maintain cardiomyocyte cellular identity. Repression of either gene results in the differentiating cardiomyocytes to move towards atrial chamber identity. The NKX2-5 mutation has also been associated with preeclampsia; though research is still being conducting in this area.[24]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000183072 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015579 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, Nagai R, Yazaki Y (May 1995). "Assignment of cardiac homeobox gene CSX to human chromosome 5q34". Genomics. 27 (1): 204–6. doi:10.1006/geno.1995.1027. PMID 7665173.
  6. ^ Turbay D, Wechsler SB, Blanchard KM, Izumo S (January 1996). "Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx". Molecular Medicine. 2 (1): 86–96. doi:10.1007/BF03402205. PMC 2230031. PMID 8900537.
  7. ^ a b "Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)".
  8. ^ Akazawa H, Komuro I (May 2003). "Roles of cardiac transcription factors in cardiac hypertrophy". Circulation Research. 92 (10): 1079–88. doi:10.1161/01.RES.0000072977.86706.23. PMID 12775656.
  9. ^ "NKX2-3 NK2 homeobox 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-13.
  10. ^ Bartlett, Veenstra, Weeks, Heather, Gert, Daniel (2010). "Examining the Cardiac NK-2 Genes in Early Heart Development". Pediatric Cardiology. 31 (3): 335–341. doi:10.1007/s00246-009-9605-0. PMC 2981039. PMID 19967350.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ "NKX2-1 NK2 homeobox 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-13.
  12. ^ Ranganayakulu G, Elliott DA, Harvey RP, Olson EN (August 1998). "Divergent roles for NK-2 class homeobox genes in cardiogenesis in flies and mice". Development. 125 (16): 3037–48. doi:10.1242/dev.125.16.3037. PMID 9671578.
  13. ^ Harvey RP (September 1996). "NK-2 homeobox genes and heart development". Developmental Biology. 178 (2): 203–16. doi:10.1006/dbio.1996.0212. PMID 8812123.
  14. ^ Li J, Cao Y, Wu Y, Chen W, Yuan Y, Ma X, Huang G (December 2015). "The expression profile analysis of NKX2-5 knock-out embryonic mice to explore the pathogenesis of congenital heart disease". Journal of Cardiology. 66 (6): 527–31. doi:10.1016/j.jjcc.2014.12.022. PMID 25818641.
  15. ^ Harrington JK, Sorabella R, Tercek A, Isler JR, Targoff KL (September 2017). "Nkx2.5 is essential to establish normal heart rate variability in the zebrafish embryo". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 313 (3): R265–R271. doi:10.1152/ajpregu.00223.2016. PMC 5625277. PMID 28615160.
  16. ^ Wang J, Jin Y, Cattini PA (February 2017). "Expression of the Cardiac Maintenance and Survival Factor FGF-16 Gene Is Regulated by Csx/Nkx2.5 and Is an Early Target of Doxorubicin Cardiotoxicity". DNA and Cell Biology. 36 (2): 117–126. doi:10.1089/dna.2016.3507. PMID 27929351.
  17. ^ a b Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature. 424 (6947): 443–7. Bibcode:2003Natur.424..443G. doi:10.1038/nature01827. PMID 12845333. S2CID 4304709.
  18. ^ Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (September 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". The EMBO Journal. 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC 1170200. PMID 9312027.
  19. ^ 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". The Journal of Biological Chemistry. 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
  20. ^ 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". Nature Genetics. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700. S2CID 13250085.
  21. ^ Carlson B (2013). Human Embryology and Developmental Biology. Saunders. pp. 104–105, 425.
  22. ^ Bodmer R (July 1993). "The gene tinman is required for specification of the heart and visceral muscles in Drosophila". Development. 118 (3): 719–29. doi:10.1242/dev.118.3.719. PMID 7915669.
  23. ^ Winslow R. "In 'Tinman' Gene, Scientists See Root Of 2 Heart Defects". Wall Street Journal.
  24. ^ Fugate E. "Developing Genetic Therapies for Congenital Heart Defects". www.muschealth.org. Archived from the original on 2016-04-12. Retrieved 2016-04-14.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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