TY - JOUR
T1 - The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation
AU - Yamagishi, Hiroyuki
AU - Yamagishi, Chihiro
AU - Nakagawa, Osamu
AU - Harvey, Richard P.
AU - Olson, Eric N.
AU - Srivastava, Deepak
N1 - Funding Information:
We thank R. S. Ross and K. R. Chien for MLC2V-lacZ transgenic mice, C. E. Seidman and B. G. Bruneau for Tbx5 and Irx4 probes, and S. Y. Tsai for COUP-TFII probe; S. Johnson for manuscript and figure preparation; T. Justus for technical assistance; and members of the Srivastava lab for helpful discussions. We also thank members of the Molecular Pathology Core (C. Pomajzl, J. Shelton, and J. Richardson) for assistance with section in situ hybridizations. This work was supported by grants from the NHLBI/NIH (1-P50-HL61033-01, 1-R01-HL62591-01, 5-R01-HL57181-04), March of Dimes Birth Defects Foundation and Smile Train, Inc. (to D.S.). O.N. was supported by the Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Japan Heart Foundation & Bayer Yakuhin Research Grant Abroad, Uehara Memorial Foundation and Yamanouchi Foundation for Research on Metabolic Disorders. E.N.O. was supported by grants from the NIH/NHLBI, the D. W. Reynolds Center for Clinical Cardiovascular Research and the McGowan Charitable Trust.
PY - 2001/11/15
Y1 - 2001/11/15
N2 - Nkx2.5/Csx and dHAND/Hand2 are conserved transcription factors that are coexpressed in the precardiac mesoderm and early heart tube and control distinct developmental events during cardiogenesis. To understand whether Nkx2.5 and dHAND may function in overlapping genetic pathways, we generated mouse embryos lacking both Nkx2.5 and dHAND. Mice heterozygous for mutant alleles of Nkx2.5 and dHAND were viable. Although single Nkx2.5 or dHAND mutants have a morphological atrial and single ventricular chamber, Nkx2.5-/-dHAND-/- mutants had only a single cardiac chamber which was molecularly defined as the atrium. Complete ventricular dysgenesis was observed in Nkx2.5-/-dHAND-/- mutants; however, a precursor pool of ventricular cardiomyocytes was identified on the ventral surface of the heart tube. Because Nkx2.5 mutants failed to activate eHAND expression even in the early precardiac mesoderm, the Nkx2.5-/-dHAND-/- phenotype appears to reflect an effectively null state of dHAND and eHAND. Cell fate analysis in dHAND mutants suggests a role of HAND genes in survival and expansion of the ventricular segment, but not in specification of ventricular cardiomyocytes. Our molecular analyses also revealed the cooperative regulation of the homeodomain protein, Irx4, by Nkx2.5 and dHAND. These studies provide the first demonstration of gene mutations that result in ablation of the entire ventricular segment of the mammalian heart, and reveal essential transcriptional pathways for ventricular formation.
AB - Nkx2.5/Csx and dHAND/Hand2 are conserved transcription factors that are coexpressed in the precardiac mesoderm and early heart tube and control distinct developmental events during cardiogenesis. To understand whether Nkx2.5 and dHAND may function in overlapping genetic pathways, we generated mouse embryos lacking both Nkx2.5 and dHAND. Mice heterozygous for mutant alleles of Nkx2.5 and dHAND were viable. Although single Nkx2.5 or dHAND mutants have a morphological atrial and single ventricular chamber, Nkx2.5-/-dHAND-/- mutants had only a single cardiac chamber which was molecularly defined as the atrium. Complete ventricular dysgenesis was observed in Nkx2.5-/-dHAND-/- mutants; however, a precursor pool of ventricular cardiomyocytes was identified on the ventral surface of the heart tube. Because Nkx2.5 mutants failed to activate eHAND expression even in the early precardiac mesoderm, the Nkx2.5-/-dHAND-/- phenotype appears to reflect an effectively null state of dHAND and eHAND. Cell fate analysis in dHAND mutants suggests a role of HAND genes in survival and expansion of the ventricular segment, but not in specification of ventricular cardiomyocytes. Our molecular analyses also revealed the cooperative regulation of the homeodomain protein, Irx4, by Nkx2.5 and dHAND. These studies provide the first demonstration of gene mutations that result in ablation of the entire ventricular segment of the mammalian heart, and reveal essential transcriptional pathways for ventricular formation.
KW - Cardiac development
KW - Congenital heart disease
KW - Nkx2.5
KW - Transcriptional regulation
KW - dHAND
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U2 - 10.1006/dbio.2001.0417
DO - 10.1006/dbio.2001.0417
M3 - Article
C2 - 11784028
AN - SCOPUS:0035891429
SN - 0012-1606
VL - 239
SP - 190
EP - 203
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -