Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Feb 3;16(3):515–522. doi: 10.1093/emboj/16.3.515

D-mef2 is a target for Tinman activation during Drosophila heart development.

K Gajewski 1, Y Kim 1, Y M Lee 1, E N Olson 1, R A Schulz 1
PMCID: PMC1169655  PMID: 9034334

Abstract

The NK-type homeobox gene tinman and the MADS box gene D-mef2 encode transcription factors required for the development and differentiation of the Drosophila heart, and closely related genes regulate cardiogenesis in vertebrates. Genetic analyses indicate that tinman and D-mef2 act at early and late steps, respectively, in the cardiogenic lineage. However, it is unknown whether regulatory interactions exist between these developmental control genes. We show that D-mef2 expression in the developing Drosophila heart requires a novel upstream enhancer containing two Tinman binding sites, both of which are essential for enhancer function in cardiac muscle cells. Transcriptional activity of this cardiac enhancer is dependent on tinman function, and ectopic Tinman expression activates the enhancer outside the cardiac lineage. These results define the only known in vivo target for transcriptional activation by Tinman and demonstrate that D-mef2 lies directly downstream of tinman in the genetic cascade controlling heart formation in Drosophila.

Full Text

The Full Text of this article is available as a PDF (288.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Azpiazu N., Frasch M. tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila. Genes Dev. 1993 Jul;7(7B):1325–1340. doi: 10.1101/gad.7.7b.1325. [DOI] [PubMed] [Google Scholar]
  2. Bodmer R., Jan L. Y., Jan Y. N. A new homeobox-containing gene, msh-2, is transiently expressed early during mesoderm formation of Drosophila. Development. 1990 Nov;110(3):661–669. doi: 10.1242/dev.110.3.661. [DOI] [PubMed] [Google Scholar]
  3. Bodmer R. The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development. 1993 Jul;118(3):719–729. doi: 10.1242/dev.118.3.719. [DOI] [PubMed] [Google Scholar]
  4. Borkowski O. M., Brown N. H., Bate M. Anterior-posterior subdivision and the diversification of the mesoderm in Drosophila. Development. 1995 Dec;121(12):4183–4193. doi: 10.1242/dev.121.12.4183. [DOI] [PubMed] [Google Scholar]
  5. Bour B. A., O'Brien M. A., Lockwood W. L., Goldstein E. S., Bodmer R., Taghert P. H., Abmayr S. M., Nguyen H. T. Drosophila MEF2, a transcription factor that is essential for myogenesis. Genes Dev. 1995 Mar 15;9(6):730–741. doi: 10.1101/gad.9.6.730. [DOI] [PubMed] [Google Scholar]
  6. Buchberger A., Pabst O., Brand T., Seidl K., Arnold H. H. Chick NKx-2.3 represents a novel family member of vertebrate homologues to the Drosophila homeobox gene tinman: differential expression of cNKx-2.3 and cNKx-2.5 during heart and gut development. Mech Dev. 1996 May;56(1-2):151–163. doi: 10.1016/0925-4773(96)00521-7. [DOI] [PubMed] [Google Scholar]
  7. Durocher D., Chen C. Y., Ardati A., Schwartz R. J., Nemer M. The atrial natriuretic factor promoter is a downstream target for Nkx-2.5 in the myocardium. Mol Cell Biol. 1996 Sep;16(9):4648–4655. doi: 10.1128/mcb.16.9.4648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Evans S. M., Yan W., Murillo M. P., Ponce J., Papalopulu N. 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):3889–3899. doi: 10.1242/dev.121.11.3889. [DOI] [PubMed] [Google Scholar]
  9. Harvey R. P. NK-2 homeobox genes and heart development. Dev Biol. 1996 Sep 15;178(2):203–216. doi: 10.1006/dbio.1996.0212. [DOI] [PubMed] [Google Scholar]
  10. Jiménez F., Martin-Morris L. E., Velasco L., Chu H., Sierra J., Rosen D. R., White K. vnd, a gene required for early neurogenesis of Drosophila, encodes a homeodomain protein. EMBO J. 1995 Jul 17;14(14):3487–3495. doi: 10.1002/j.1460-2075.1995.tb07355.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Komuro I., Izumo S. Csx: a murine homeobox-containing gene specifically expressed in the developing heart. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8145–8149. doi: 10.1073/pnas.90.17.8145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lawrence P. A., Bodmer R., Vincent J. P. Segmental patterning of heart precursors in Drosophila. Development. 1995 Dec;121(12):4303–4308. doi: 10.1242/dev.121.12.4303. [DOI] [PubMed] [Google Scholar]
  13. Lee K. H., Xu Q., Breitbart R. E. A new tinman-related gene, nkx2.7, anticipates the expression of nkx2.5 and nkx2.3 in zebrafish heart and pharyngeal endoderm. Dev Biol. 1996 Dec 15;180(2):722–731. doi: 10.1006/dbio.1996.0341. [DOI] [PubMed] [Google Scholar]
  14. Lilly B., Galewsky S., Firulli A. B., Schulz R. A., Olson E. N. D-MEF2: a MADS box transcription factor expressed in differentiating mesoderm and muscle cell lineages during Drosophila embryogenesis. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5662–5666. doi: 10.1073/pnas.91.12.5662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lilly B., Zhao B., Ranganayakulu G., Paterson B. M., Schulz R. A., Olson E. N. Requirement of MADS domain transcription factor D-MEF2 for muscle formation in Drosophila. Science. 1995 Feb 3;267(5198):688–693. doi: 10.1126/science.7839146. [DOI] [PubMed] [Google Scholar]
  16. Lin M. H., Nguyen H. T., Dybala C., Storti R. V. Myocyte-specific enhancer factor 2 acts cooperatively with a muscle activator region to regulate Drosophila tropomyosin gene muscle expression. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4623–4628. doi: 10.1073/pnas.93.10.4623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lints T. J., Parsons L. M., Hartley L., Lyons I., Harvey R. P. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development. 1993 Oct;119(2):419–431. doi: 10.1242/dev.119.2.419. [DOI] [PubMed] [Google Scholar]
  18. Lyons I., Parsons L. M., Hartley L., Li R., Andrews J. E., Robb L., Harvey R. P. 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):1654–1666. doi: 10.1101/gad.9.13.1654. [DOI] [PubMed] [Google Scholar]
  19. Mellerick D. M., Nirenberg M. Dorsal-ventral patterning genes restrict NK-2 homeobox gene expression to the ventral half of the central nervous system of Drosophila embryos. Dev Biol. 1995 Oct;171(2):306–316. doi: 10.1006/dbio.1995.1283. [DOI] [PubMed] [Google Scholar]
  20. Nguyen H. T., Bodmer R., Abmayr S. M., McDermott J. C., Spoerel N. A. D-mef2: a Drosophila mesoderm-specific MADS box-containing gene with a biphasic expression profile during embryogenesis. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7520–7524. doi: 10.1073/pnas.91.16.7520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Olson E. N., Srivastava D. Molecular pathways controlling heart development. Science. 1996 May 3;272(5262):671–676. doi: 10.1126/science.272.5262.671. [DOI] [PubMed] [Google Scholar]
  22. Ranganayakulu G., Zhao B., Dokidis A., Molkentin J. D., Olson E. N., Schulz R. A. A series of mutations in the D-MEF2 transcription factor reveal multiple functions in larval and adult myogenesis in Drosophila. Dev Biol. 1995 Sep;171(1):169–181. doi: 10.1006/dbio.1995.1269. [DOI] [PubMed] [Google Scholar]
  23. Rubin G. M., Spradling A. C. Genetic transformation of Drosophila with transposable element vectors. Science. 1982 Oct 22;218(4570):348–353. doi: 10.1126/science.6289436. [DOI] [PubMed] [Google Scholar]
  24. St Johnston R. D., Gelbart W. M. Decapentaplegic transcripts are localized along the dorsal-ventral axis of the Drosophila embryo. EMBO J. 1987 Sep;6(9):2785–2791. doi: 10.1002/j.1460-2075.1987.tb02574.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Staehling-Hampton K., Hoffmann F. M., Baylies M. K., Rushton E., Bate M. dpp induces mesodermal gene expression in Drosophila. Nature. 1994 Dec 22;372(6508):783–786. doi: 10.1038/372783a0. [DOI] [PubMed] [Google Scholar]
  26. Tonissen K. F., Drysdale T. A., Lints T. J., Harvey R. P., Krieg P. A. 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):325–328. doi: 10.1006/dbio.1994.1089. [DOI] [PubMed] [Google Scholar]
  27. Tsao D. H., Gruschus J. M., Wang L. H., Nirenberg M., Ferretti J. A. Elongation of helix III of the NK-2 homeodomain upon binding to DNA: a secondary structure study by NMR. Biochemistry. 1994 Dec 20;33(50):15053–15060. doi: 10.1021/bi00254a014. [DOI] [PubMed] [Google Scholar]
  28. Wu X., Golden K., Bodmer R. Heart development in Drosophila requires the segment polarity gene wingless. Dev Biol. 1995 Jun;169(2):619–628. doi: 10.1006/dbio.1995.1174. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES