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

Research output: Contribution to journalArticlepeer-review

144 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)190-203
Number of pages14
JournalDevelopmental Biology
Volume239
Issue number2
DOIs
Publication statusPublished - 2001 Nov 15
Externally publishedYes

Keywords

  • Cardiac development
  • Congenital heart disease
  • Nkx2.5
  • Transcriptional regulation
  • dHAND

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation'. Together they form a unique fingerprint.

Cite this