Nkx2–5 Activity Is Essential for Cardiomyogenesis

The homeobox transcription factor tinman is essential for heart vessel formation in Drosophila. In contrast, mice lacking the murine homologue Nkx2–5 are defective in cardiac looping but not in cardiac myocyte development. The lack of an essential role for Nkx2–5 in cardiomyogenesis in mammalian sys...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-11, Vol.276 (45), p.42252-42258
Main Authors: Jamali, Mina, Rogerson, Parker J., Wilton, Sharon, Skerjanc, Ilona S.
Format: Article
Language:English
Subjects:
Actins - genetics
Animals
Bone Morphogenetic Protein 4
Bone Morphogenetic Proteins - analysis
Cell Line
DNA-Binding Proteins - analysis
DNA-Binding Proteins - genetics
GATA4 Transcription Factor
Heart - embryology
Homeobox Protein Nkx-2.5
Homeodomain Proteins - chemistry
Homeodomain Proteins - physiology
MEF2 Transcription Factors
Muscle, Skeletal - embryology
myogenesis
Myogenic Regulatory Factors - genetics
Neoplastic Stem Cells
Nkx2-5 protein
RNA, Messenger - analysis
Transcription Factors - analysis
Transcription Factors - genetics
Xenopus Proteins
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Summary:The homeobox transcription factor tinman is essential for heart vessel formation in Drosophila. In contrast, mice lacking the murine homologue Nkx2–5 are defective in cardiac looping but not in cardiac myocyte development. The lack of an essential role for Nkx2–5 in cardiomyogenesis in mammalian systems is most likely the result of genetic redundancy with family members. In this study, we used a dominant negative mutant of Nkx2–5, created by fusing the repressor domain of engrailed 2 to the Nkx2–5 homeodomain, termed Nkx/EnR. Expression of Nkx/EnR inhibited Me2SO-induced cardiomyogenesis in P19 cells but not skeletal myogenesis. Nkx/EnR inhibited expression of cardiomyoblast markers, such as GATA-4 and MEF2C, but not of mesoderm markers, such as Brachyury T and Wnt5b, or of skeletal lineage markers, such as MyoD and Mox1. To identify the minimal region of Nkx2–5 that can trigger cardiomyogenesis, we analyzed the activity of various Nkx2–5 deletion mutants. The C-terminal domain was not necessary for the ability of Nkx2–5 to induce cardiomyogenesis and loss of this domain did not enhance myogenesis. Therefore, Nkx2–5 function is essential for commitment of mesoderm into the cardiac muscle lineage, and the N-terminal region, together with the homeodomain, is sufficient for cardiomyogenesis in P19 cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M107814200