The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation

Hiroyuki Yamagishi, Chihiro Yamagishi, Osamu Nakagawa, Richard P. Harvey, Eric N. Olson, Deepak Srivastava

研究成果: Article査読

145 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)190-203
ページ数14
ジャーナルDevelopmental Biology
239
2
DOI
出版ステータスPublished - 2001 11 15
外部発表はい

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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