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J. Biol. Chem., Vol. 276, Issue 45, 42252-42258, November 9, 2001
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From the Department of Biochemistry, University of Western Ontario,
London, Ontario N6A 5C1, Canada
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.
Nkx2-5 Activity Is Essential for
Cardiomyogenesis*
,
*
This work was supported in part by Grant-in-aid T-4157from
the Heart and Stroke Foundation of Ontario.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Natural Sciences and Engineering Research Council
of Canada postgraduate studentship.
§
To whom correspondence should be addressed: Dept. of Biochemistry,
Medical Sciences Bldg., University of Western Ontario, London, Ontario
N6A 5C1, Canada. Tel.: 519-661-2111 (Ext. 86867); Fax:
519-661-3175; E-mail: skerjanc@uwo.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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