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 journalArticle

140 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

Fingerprint

Heart Ventricles
Mesoderm
Cardiac Myocytes
Homeodomain Proteins
Genes
Transcription Factors
Embryonic Structures
Alleles
Phenotype
Mutation

Keywords

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

ASJC Scopus subject areas

  • Developmental Biology

Cite this

The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. / Yamagishi, Hiroyuki; Yamagishi, Chihiro; Nakagawa, Osamu; Harvey, Richard P.; Olson, Eric N.; Srivastava, Deepak.

In: Developmental Biology, Vol. 239, No. 2, 15.11.2001, p. 190-203.

Research output: Contribution to journalArticle

Yamagishi, Hiroyuki ; Yamagishi, Chihiro ; Nakagawa, Osamu ; Harvey, Richard P. ; Olson, Eric N. ; Srivastava, Deepak. / The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. In: Developmental Biology. 2001 ; Vol. 239, No. 2. pp. 190-203.
@article{bc5ecb9db1ef40c79300986c08b6578d,
title = "The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation",
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.",
keywords = "Cardiac development, Congenital heart disease, dHAND, Nkx2.5, Transcriptional regulation",
author = "Hiroyuki Yamagishi and Chihiro Yamagishi and Osamu Nakagawa and Harvey, {Richard P.} and Olson, {Eric N.} and Deepak Srivastava",
year = "2001",
month = "11",
day = "15",
doi = "10.1006/dbio.2001.0417",
language = "English",
volume = "239",
pages = "190--203",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "2",

}

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

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 - dHAND

KW - Nkx2.5

KW - Transcriptional regulation

UR - http://www.scopus.com/inward/record.url?scp=0035891429&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035891429&partnerID=8YFLogxK

U2 - 10.1006/dbio.2001.0417

DO - 10.1006/dbio.2001.0417

M3 - Article

VL - 239

SP - 190

EP - 203

JO - Developmental Biology

JF - Developmental Biology

SN - 0012-1606

IS - 2

ER -