FOG-2 attenuates endothelial-to-mesenchymal transformation in the endocardial cushions of the developing heart.
Development of the heart valves is a complex process that relies on the successful remodeling of endocardial cushions. This process is dependent on a number of transcriptional regulators, including GATA4 and its interacting partner FOG-2. We have previously shown that the endocardial cushions in FOG-2 deficient mice are hyperplastic and fail to remodel appropriately, suggesting a defect late in endocardial cushion development. To elucidate this defect, we examined the later steps in endocardial cushion development including mesenchymal cell proliferation, differentiation, and apoptosis. We also measured myocardialization and endothelial-to-mesenchymal transformation (EMT) using previously described in vitro assays. We found no difference in the ability of the endocardial cushions to undergo myocardialization or in the rates of mesenchymal cell proliferation, differentiation, or apoptosis in the FOG-2 deficient cushions when compared to wild-type controls. However, using a collagen gel invasion assay, we found a 78% increase in outflow tract cushion EMT and a 35% increase in atrioventricular cushion EMT in the FOG-2 deficient mice when compared with wild-type mice. Taken together with GATA4's known role in promoting EMT, these results suggest that FOG-2 functions in cardiac valve formation as an attenuator of EMT by repressing GATA4 activity within the developing endocardial cushions.
Flagg
Alleda E
AE
Department of Medicine, University of Chicago, Section of Cardiology, 5841 S. Maryland Ave, MC6088, Chicago, IL 60637, USA.
Earley
Judy U
JU
Svensson
Eric C
EC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D004699:Endocardium / Q000166:cytology / Q000196:embryology*; D042783:Endothelial Cells / Q000166:cytology; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D014157:Transcription Factors; C492170:Zfpm2 protein, mouse