Home LiteratureArticle Details
PMID: 8756621 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The atrial natriuretic factor promoter is a downstream target for Nkx-2.5 in the myocardium.

Molecular and cellular biology ·Vol. 16 ·No. 9 ·1996-09-00 ·Pages 4648-55

Durocher D, Chen CY, Ardati A, Schwartz RJ, Nemer M

Abstract

The recently described NK2 family of homeodomain proteins are key developmental regulators. In Drosophila melanogaster, two members of this family, bagpipe and tinman, are required for visceral and cardiac mesoderm formation, respectively. In vertebrates, tinman appears to represent a family of closely related NK2 genes, including Nkx-2.5, that are expressed at an early stage in precardiac cells. Consistent with a role for Nkx-2.5 in heart development, inactivation of the Nkx-2.5 gene in mice causes severe cardiac malformations and embryonic lethality. However, little is known about the molecular action of Nkx-2.5 and its targets in cardiac muscle. In this paper, we report the identification and characterization of a functional and highly conserved Nkx-2.5 response element, termed the NKE, in the proximal region of the cardiac atrial natriuretic factor (ANF) promoter. The NKE is composed of two near-consensus NK2 binding sites that are each able to bind purified Nkx-2.5. The NKE is sufficient to confer cardiac cell-specific activity to a minimal TATA-containing promoter and is required for Nkx-2.5 activation of the ANF promoter in heterologous cells. Interestingly, in primary cardiocyte cultures, the NKE contributes to ANF promoter activity in a chamber- and developmental stage-specific manner, suggesting that Nkx-2.5 and/or other related cardiac proteins may play a role in chamber specification. This work provides the identification of a direct target for NK2 homeoproteins in the heart and lays the foundation for further molecular analyses of the role of Nkx-2.5 and other NK2 proteins in cardiac development.

MeSH Terms
Animals Atrial Natriuretic Factor/genetics Base Sequence Binding Sites Cells, Cultured Consensus Sequence DNA/genetics,metabolism Fetal Heart/growth & development Gene Expression Regulation, Developmental Heart Atria Heart Ventricles Homeobox Protein Nkx-2.5 Homeodomain Proteins/metabolism Molecular Sequence Data Muscle Proteins/metabolism Myocardium/metabolism Promoter Regions, Genetic Rats Rats, Sprague-Dawley TATA Box Transcription Factors Xenopus Proteins
Chemicals
Homeobox Protein Nkx-2.5 Homeodomain Proteins Muscle Proteins NKX2-5 protein, human Transcription Factors Xenopus Proteins Atrial Natriuretic Factor DNA
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Durocher D
Laboratoire de Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, Quebec, Canada.
Chen C Y
Ardati A
Schwartz R J
Nemer M
References (50)
50 references, click to expand
  1. Redundant domains contribute to the transcriptional activity of the thyroid transcription factor 1.
    J Biol Chem. 1995 Nov 3;270(44):26649-56 PMID: 7592890
  2. Definition of the DNA-binding specificity of TTF-1 homeodomain by chromatographic selection of binding sequences.
    Biochem Biophys Res Commun. 1995 Aug 24;213(3):781-8 PMID: 7654238
  3. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.
    Genes Dev. 1996 Jan 1;10(1):60-9 PMID: 8557195
  4. The nucleotide sequence of a rat myosin light chain 2 gene.
    Nucleic Acids Res. 1984 Sep 25;12(18):7175-86 PMID: 6091059
  5. The gene for rat atrial natriuretic factor.
    J Biol Chem. 1985 Apr 25;260(8):4568-71 PMID: 2985557
  6. Duplicated CArG box domains have positive and mutually dependent regulatory roles in expression of the human alpha-cardiac actin gene.
    Mol Cell Biol. 1987 Aug;7(8):2803-13 PMID: 2823106
  7. Localized expression of the atrial natriuretic factor gene during cardiac embryogenesis.
    Genes Dev. 1987 Sep;1(7):693-8 PMID: 2962900
  8. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice.
    Science. 1988 Feb 26;239(4843):1029-33 PMID: 2964082
  9. The structure and function of the homeodomain.
    Biochim Biophys Acta. 1989 Jul 28;989(1):25-48 PMID: 2568852
  10. Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice.
    Mol Cell Biol. 1989 Aug;9(8):3393-9 PMID: 2796990
  11. Drosophila NK-homeobox genes.
    Proc Natl Acad Sci U S A. 1989 Oct;86(20):7716-20 PMID: 2573058
  12. Complete sequence and organization of the human cardiac beta-myosin heavy chain gene.
    Nucleic Acids Res. 1990 Jun 25;18(12):3647-51 PMID: 2362820
  13. Protein--DNA contacts in the structure of a homeodomain--DNA complex determined by nuclear magnetic resonance spectroscopy in solution.
    EMBO J. 1990 Oct;9(10):3085-92 PMID: 1976507
  14. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity.
    EMBO J. 1990 Nov;9(11):3631-9 PMID: 1976511
  15. Planarian homeobox genes: cloning, sequence analysis, and expression.
    Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7338-42 PMID: 1714599
  16. cis-dominance of rat atrial natriuretic factor gene regulatory sequences in transgenic mice.
    Can J Physiol Pharmacol. 1991 Oct;69(10):1486-92 PMID: 1723347
  17. Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain.
    Neuron. 1992 Feb;8(2):241-55 PMID: 1346742
  18. A single transcription factor binds to two divergent sequence elements with a common function in cardiac myosin light chain-2 promoter.
    Mol Cell Biol. 1992 Mar;12(3):1107-16 PMID: 1545792
  19. A ubiquitous factor (HF-1a) and a distinct muscle factor (HF-1b/MEF-2) form an E-box-independent pathway for cardiac muscle gene expression.
    Mol Cell Biol. 1992 Apr;12(4):1469-79 PMID: 1532229
  20. fos/jun repression of cardiac-specific transcription in quiescent and growth-stimulated myocytes is targeted at a tissue-specific cis element.
    Mol Cell Biol. 1993 Jan;13(1):600-12 PMID: 8417355
  21. Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle.
    Mol Cell Biol. 1993 Feb;13(2):1264-72 PMID: 8423791
  22. Expression of the alpha-myosin heavy chain gene in the heart is regulated in part by an E-box-dependent mechanism.
    J Biol Chem. 1993 Feb 5;268(4):2602-9 PMID: 8428936
  23. In vivo analysis of the murine beta-myosin heavy chain gene promoter.
    J Biol Chem. 1993 Mar 5;268(7):5332-8 PMID: 8444907
  24. Gradients of transgene expression directed by the human myoglobin promoter in the developing mouse heart.
    Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1726-30 PMID: 8446585
  25. tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila.
    Genes Dev. 1993 Jul;7(7B):1325-40 PMID: 8101173
  26. Csx: a murine homeobox-containing gene specifically expressed in the developing heart.
    Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8145-9 PMID: 7690144
  27. Heart-specific targeting of firefly luciferase by the myosin light chain-2 promoter and developmental regulation in transgenic mice.
    Circ Res. 1993 Oct;73(4):629-38 PMID: 8370121
  28. Genomic organization and expression of the planarian homeobox genes Dth-1 and Dth-2.
    Development. 1993 May;118(1):241-53 PMID: 8104142
  29. A nuclear pathway for alpha 1-adrenergic receptor signaling in cardiac cells.
    EMBO J. 1993 Dec 15;12(13):5131-9 PMID: 8262057
  30. Developmental stage-specific regulation of atrial natriuretic factor gene transcription in cardiac cells.
    Mol Cell Biol. 1994 Jan;14(1):777-90 PMID: 8264645
  31. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants.
    Development. 1993 Oct;119(2):419-31 PMID: 7904557
  32. Muscle-enriched TEF-1 isoforms bind M-CAT elements from muscle-specific promoters and differentially activate transcription.
    J Biol Chem. 1994 Feb 4;269(5):3147-50 PMID: 8106348
  33. XNkx-2.5, a Xenopus gene related to Nkx-2.5 and tinman: evidence for a conserved role in cardiac development.
    Dev Biol. 1994 Mar;162(1):325-8 PMID: 7545912
  34. A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription.
    Mol Cell Biol. 1994 May;14(5):3115-29 PMID: 8164667
  35. The avian cardiac alpha-actin promoter is regulated through a pair of complex elements composed of E boxes and serum response elements that bind both positive- and negative-acting factors.
    J Biol Chem. 1994 Apr 29;269(17):12731-40 PMID: 8175685
  36. Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene.
    Mol Cell Biol. 1994 Jul;14(7):4947-57 PMID: 8007990
  37. An M-CAT binding factor and an RSRF-related A-rich binding factor positively regulate expression of the alpha-cardiac myosin heavy-chain gene in vivo.
    Mol Cell Biol. 1994 Aug;14(8):5056-65 PMID: 8035789
  38. Homeodomain-DNA recognition.
    Cell. 1994 Jul 29;78(2):211-23 PMID: 8044836
  39. The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis.
    Mol Cell Biol. 1994 Sep;14(9):5671-81 PMID: 8065304
  40. The gene tinman is required for specification of the heart and visceral muscles in Drosophila.
    Development. 1993 Jul;118(3):719-29 PMID: 7915669
  41. Lox10, a member of the NK-2 homeobox gene class, is expressed in a segmental pattern in the endoderm and in the cephalic nervous system of the leech Helobdella.
    Development. 1993 Jul;118(3):877-92 PMID: 7915671
  42. The Caenorhabditis elegans NK-2 class homeoprotein CEH-22 is involved in combinatorial activation of gene expression in pharyngeal muscle.
    Development. 1994 Aug;120(8):2175-86 PMID: 7925019
  43. The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells.
    Mol Cell Biol. 1994 Nov;14(11):7517-26 PMID: 7935467
  44. Homeodomain proteins.
    Annu Rev Biochem. 1994;63:487-526 PMID: 7979246
  45. Myosin light chain 3F regulatory sequences confer regionalized cardiac and skeletal muscle expression in transgenic mice.
    J Cell Biol. 1995 Apr;129(2):383-96 PMID: 7721942
  46. Identification of novel DNA binding targets and regulatory domains of a murine tinman homeodomain factor, nkx-2.5.
    J Biol Chem. 1995 Jun 30;270(26):15628-33 PMID: 7797561
  47. vnd, a gene required for early neurogenesis of Drosophila, encodes a homeodomain protein.
    EMBO J. 1995 Jul 17;14(14):3487-95 PMID: 7628450
  48. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.
    Genes Dev. 1995 Jul 1;9(13):1654-66 PMID: 7628699
  49. Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1.
    J Clin Invest. 1995 Aug;96(2):781-5 PMID: 7635972
  50. tinman, a Drosophila homeobox gene required for heart and visceral mesoderm specification, may be represented by a family of genes in vertebrates: XNkx-2.3, a second vertebrate homologue of tinman.
    Development. 1995 Nov;121(11):3889-99 PMID: 8582297
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.16.9.4648
Published
1996-09-00
Pages
4648-55
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231464
Subset
IM
Grants
PHS HHS · R0150422 · United States
External Links
PubMed source DOI: 10.1128/MCB.16.9.4648 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2