Cardiac Expression of the Ventricle-Specific Homeobox Gene Irx4 Is Modulated by Nkx2-5 and dHand

We report the isolation and characterization of the cDNAs encoded by the murine and human homeobox genes, Irx4 (Iroquois homeobox gene 4). Mouse and human Irx4 proteins are highly conserved (83%) and their 63-aa homeodomain is more than 93% identical to that of the Drosophila Iroquois patterning gen...

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Bibliographic Details
Published in:Developmental biology 2000-01, Vol.217 (2), p.266-277
Main Authors: Bruneau, Benoit G., Bao, Zheng-Zheng, Tanaka, Makoto, Schott, Jean-Jacques, Izumo, Seigo, Cepko, Constance L., Seidman, J.G., Seidman, Christine E.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Basic Helix-Loop-Helix Transcription Factors
cardiac development
chromosome 13
chromosome 5
Cloning, Molecular
Conserved Sequence
dHand protein
DNA-Binding Proteins - metabolism
Evolution, Molecular
Heart Defects, Congenital - genetics
Heart Ventricles - embryology
homeobox gene
Homeobox Protein Nkx-2.5
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Irx4 gene
IRX4 protein
MEF2c gene
Mice
Mice, Mutant Strains
Molecular Sequence Data
Nkx2-5 protein
patterning
RXR^a gene
Sequence Homology, Amino Acid
Transcription Factors - metabolism
Xenopus Proteins
Zebrafish Proteins
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Summary:We report the isolation and characterization of the cDNAs encoded by the murine and human homeobox genes, Irx4 (Iroquois homeobox gene 4). Mouse and human Irx4 proteins are highly conserved (83%) and their 63-aa homeodomain is more than 93% identical to that of the Drosophila Iroquois patterning genes. Human IRX4 maps to chromosome 5p15.3, which is syntenic to murine chromosome 13. Irx4 transcripts are present in the developing central nervous system, skin, and vibrissae, but are predominantly expressed in the cardiac ventricles. In mice at embryonic day (E) 7.5, Irx4 transcripts are found in the chorion and at low levels in a discrete anterior domain of the cardiac primordia. During the formation of the linear heart tube and its subsequent looping (E8.0–8.5), Irx4 expression is restricted to the ventricular segment and is absent from both the posterior (eventual atrial) and the anterior (eventual outflow tract) segments of the heart. Throughout all subsequent stages in which the chambers of the heart become morphologically distinct (E8.5–11) and into adulthood, cardiac Irx4 expression is found exclusively in the ventricular myocardium. Irx4 gene expression was also assessed in embryos with aberrant cardiac development: mice lacking RXRα or MEF2c have normal Irx4 expression, but mice lacking the homeobox transcription factor Nkx2-5 (Csx) have markedly reduced levels of Irx4 transcripts. dHand-null embryos initiate Irx4 expression, but cannot maintain normal levels. These data indicate that the homeobox gene Irx4 is likely to be an important mediator of ventricular differentiation during cardiac development, which is downstream of Nkx2-5 and dHand.
ISSN:0012-1606
1095-564X
DOI:10.1006/dbio.1999.9548