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dc.contributor.authorRivera-Feliciano, José
dc.contributor.authorLee, Kyu-Ho
dc.contributor.authorKong, Sek Won
dc.contributor.authorRajagopal, Satish
dc.contributor.authorMa, Qing
dc.contributor.authorSpringer, Zhangli
dc.contributor.authorIzumo, Seigo
dc.contributor.authorTabin, Clifford J.
dc.contributor.authorPu, William T.
dc.date.accessioned2019-10-14T16:05:50Z
dc.date.issued2006
dc.identifier.citationRivera-Feliciano, J. 2006. “Development of Heart Valves Requires Gata4 Expression in Endothelial-Derived Cells.” Development 133 (18): 3607–18. doi:10.1242/dev.02519.
dc.identifier.issn0950-1991
dc.identifier.issn1477-9129
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41543027*
dc.description.abstractCardiac 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 the mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in the formation of portions of the atrial and ventricular septae, and the generation of thin, pliable valves. Gata4, which encodes a zinc finger transcription factor, 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 a 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.
dc.language.isoen_US
dc.publisherCompany of Biologists
dash.licenseLAA
dc.titleDevelopment of heart valves requires Gata4 expression in endothelial-derived cells
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalDevelopment (Cambridge, England)
dash.depositing.authorKong, Sek Won Won::231dbf42b8f730cea07bc0729dabe2e1::600
dc.date.available2019-10-14T16:05:50Z
dash.workflow.comments1Science Serial ID 34650
dc.identifier.doi10.1242/dev.02519
dash.source.volume133;18
dash.source.page3607


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