The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner.
The basic helix-loop-helix transcription factors Hand1 and Hand2 display dynamic and spatially restricted expression patterns in the developing heart. Mice that lack Hand2 die at embryonic day 10.5 from right ventricular hypoplasia and vascular defects, whereas mice that lack Hand1 die at embryonic day 8.5 from placental and extra-embryonic abnormalities that preclude analysis of its potential role in later stages of heart development. To determine the cardiac functions of Hand1, we generated mice harboring a conditional Hand1-null allele and excised the gene by cardiac-specific expression of Cre recombinase. Embryos homozygous for the cardiac Hand1 gene deletion displayed defects in the left ventricle and endocardial cushions, and exhibited dysregulated ventricular gene expression. However, these embryos survived until the perinatal period when they died from a spectrum of cardiac abnormalities. Creation of Hand1/2 double mutant mice revealed gene dose-sensitive functions of Hand transcription factors in the control of cardiac morphogenesis and ventricular gene expression. These findings demonstrate that Hand factors play pivotal and partially redundant roles in cardiac morphogenesis, cardiomyocyte differentiation and cardiac-specific transcription.
McFadden
David G
DG
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Barbosa
Ana C
AC
Richardson
James A
JA
Schneider
Michael D
MD
Srivastava
Deepak
D
Olson
Eric N
EN
D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000502:physiology; D017353:Gene Deletion; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006720:Homozygote; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D029961:Zebrafish Proteins; D001616:beta-Galactosidase / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D001616:beta-Galactosidase; C095572:Hand1 protein, mouse; C498766:Hand2 protein, mouse; C484469:Nkx2-5 protein, mouse; C410915:hand2 protein, zebrafish; C097341:helix-loop-helix protein, eHAND