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Identification of a Genetic Locus for Atrioventricular Valve Formation
K. Kaneko, X. Li, X. Zhang, J. Lamberti*, S. W. Jamieson*, P. A. Thistlethwaite*. University of California, San Diego, San Diego, CA,
BACKGROUND: Atrioventricular canal defects account for 4% of all congenital heart anomalies. They arise from failure of endocardial cushion formation, a process dependent on transition of endothelial cells into clustered mesenchymal cells in the mid atrioventricular septum. To date, the genetic signals necessary for atrioventricular canal defects are poorly understood. We hypothesized that bone morphogenetic protein signaling in heart endothelial cells may be crucial to this process.
METHODS: In order to study the role of bone morphogenetic protein receptors (BMPR) in the developing heart, we created knockout mice with inactivation of BMPR1A selectively in heart endothelium. Two strains of null mice were created: one with constitutive endothelial-specific knockout of BMPR1A and one with time-inducible, endothelial-specific knockout of BMPR1A. Embryos and animals were analyzed by microscopy, whole mount and section RNA in situ hybridization, immunohistochemistry, and microangiography.
RESULTS: Animals with null mutation of BMPR1A were embryonic lethal at E12.0 and demonstrated absence of endocardial cushion formation. Embryos failed to form atrioventricular valves and adjacent septae. Endothelial knockout of BMPR1A did not affect outflow tract, arch, or pulmonary artery development. Using time-inducible cell-specific knockout mice, we show that BMPR1A has three functions in the developing atrioventricular canal: to stimulate the formation of cardiac jelly, to induce endocardial endothelial-mesenchymal transition, and to pattern the septal myocardium into endocardial cushions. We demonstrate by lineage mapping that these processes are dependent on BMPR1A-induced expression of the transcription factor, 1d1.
CONCLUSIONS: Endocardial cushion formation is dependent on cell-specific expression of BMPR1A and its downstream effector, Id1. Our results suggest that BMPR1A-mediated signaling is a part of a critical pathway involved in pathogenesis of atrioventricular septal and valve malformations, which are among the most common congenital cardiac birth defects in humans.
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