TY - JOUR
T1 - GATA4 is a dosage-sensitive regulator of cardiac morphogenesis
AU - Pu, William T.
AU - Ishiwata, Takahiro
AU - Juraszek, Amy L.
AU - Ma, Qing
AU - Izumo, Seigo
N1 - Funding Information:
We thank Maria Rivera for excellent technical assistance. Gene targeting and injection of blastocysts into ES cells was performed by the Gene Manipulation Core at Children's Hospital. This work was supported by grants from the NIH NHLBI [SCOR in Pediatric Heart Disease (P50 HL61036) and K08 HL004387-04] and from the Hood Foundation.
PY - 2004/11/1
Y1 - 2004/11/1
N2 - Normal heart development is orchestrated by a set of highly conserved transcription factors that includes GATA4, Nkx2-5, and Tbx5. Heterozygous mutation of each of these genes causes congenital heart disease in humans. In mouse models, haploinsufficiency for Nkx2-5 or Tbx5 resulted in an increased incidence of structural heart disease, confirming that normal heart development is sensitive to small changes in expression levels of Nkx2-5 and Tbx5. However, mice haploinsufficient for GATA4 have not been reported to have cardiac abnormalities. We generated two new GATA4 alleles, GATA4H and GATA4flox. GATA4flox/flox embryos expressed 50% less GATA4 protein in the heart and survived normally. In contrast, GATA4H/H embryos expressed 70% less GATA4 protein in the heart and died between days 13.5 and 16.5 of gestation. These embryos had common atrioventricular canal (CAVC), double outlet right ventricle (DORV), hypoplastic ventricular myocardium, and normal coronary vasculature. Myocardial hypoplasia was associated with diminished cardiomyocyte proliferation. Hemodynamic measurements demonstrated that these embryos had normal systolic function, severe diastolic dysfunction, and atrioventricular regurgitation. Surprisingly, expression levels of the putative GATA4 target genes ANF, BNP, MEF2C, Nkx2-5, cyclin D2, and BMP4 were unchanged in mutant hearts, suggesting that GATA4 is not a dose-limiting regulator of the expression of these genes during later stages of embryonic cardiac development. These data demonstrate that multiple aspects of embryonic cardiac morphogenesis and function are exquisitely sensitive to small changes in GATA4 expression levels.
AB - Normal heart development is orchestrated by a set of highly conserved transcription factors that includes GATA4, Nkx2-5, and Tbx5. Heterozygous mutation of each of these genes causes congenital heart disease in humans. In mouse models, haploinsufficiency for Nkx2-5 or Tbx5 resulted in an increased incidence of structural heart disease, confirming that normal heart development is sensitive to small changes in expression levels of Nkx2-5 and Tbx5. However, mice haploinsufficient for GATA4 have not been reported to have cardiac abnormalities. We generated two new GATA4 alleles, GATA4H and GATA4flox. GATA4flox/flox embryos expressed 50% less GATA4 protein in the heart and survived normally. In contrast, GATA4H/H embryos expressed 70% less GATA4 protein in the heart and died between days 13.5 and 16.5 of gestation. These embryos had common atrioventricular canal (CAVC), double outlet right ventricle (DORV), hypoplastic ventricular myocardium, and normal coronary vasculature. Myocardial hypoplasia was associated with diminished cardiomyocyte proliferation. Hemodynamic measurements demonstrated that these embryos had normal systolic function, severe diastolic dysfunction, and atrioventricular regurgitation. Surprisingly, expression levels of the putative GATA4 target genes ANF, BNP, MEF2C, Nkx2-5, cyclin D2, and BMP4 were unchanged in mutant hearts, suggesting that GATA4 is not a dose-limiting regulator of the expression of these genes during later stages of embryonic cardiac development. These data demonstrate that multiple aspects of embryonic cardiac morphogenesis and function are exquisitely sensitive to small changes in GATA4 expression levels.
KW - Cardiac morphogenesis
KW - GATA4
KW - Heart
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U2 - 10.1016/j.ydbio.2004.08.008
DO - 10.1016/j.ydbio.2004.08.008
M3 - Article
C2 - 15464586
AN - SCOPUS:4644358238
SN - 0012-1606
VL - 275
SP - 235
EP - 244
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -