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Series GSE5298 Query DataSets for GSE5298
Status Public on Jul 14, 2006
Title Development of heart valves requires Gata4 expression in endothelial-derived cells
Organism Mus musculus
Experiment type Expression profiling by array
Summary Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in formation of portions of the atrial and ventricular septae, and generation of thin, pliable valves. The transcription factor Gata4 is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling.
Keywords: genetic modification
Overall design To further investigate the role of Gata4 in EC development, we specifically inactivated Gata4 in endothelium and endothelium-derived cushion mesenchyme. All mice were maintained in a mixed C57BL6/129 genetic background. Gata4wt/flox; T2Cre+ mice were crossed with Gata4flox/flox mice to yield Gata4flox/flox (CONTROL); T2Cre+ (Gata4T2del) (MUTANT) mice.
For RNA analysis, four mutant and four control RNA samples were prepared (Pico-Pure RNA Isolation Kit, Arcturus), each consisting of 10 microdissected AVCs. Probe was prepared from 50 ng total RNA using an isothermal amplification protocol (NuGen), and hybridized to Affymetrix Mouse 430 2.0 microarrays. Two control samples were excluded because of excessive noise.
Contributor(s) Rivera-Feliciano J, Lee K, Kong S, Rajagopal S, Ma Q, Springer Z, Izumo S, Tabin CJ, Pu WT
Citation(s) 16914500
Submission date Jul 12, 2006
Last update date Feb 11, 2019
Contact name Sek Won Kong
Phone 617-919-2689
Organization name Boston Children's Hospital
Department Informatics Program
Lab EN137
Street address 300 Longwood Avenue
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (8)
GSM120064 AVC_control_rep1
GSM120065 AVC_control_rep2
GSM120066 AVC_control_rep3
BioProject PRJNA95397

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE5298_RAW.tar 50.1 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file

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