Genetic regulation of heart-valve development

Jose Rivera-Feliciano

This dissertation explores vertebrate heart development, focusing on the genetic pathways regulating heart-valve morphogenesis and how abnormal deployment of these pathways results in disease. First, this dissertation examines the role of Bone morphogenesic protein 2 (Bmp2) in establishing the heart-valve inducing field. Bmp2 is expressed amid developing atria and ventricles in myocardium. Earlier work showed that myocardium secretes a factor(s) that induces the underlying endothelium to form mesenchyme. This mesenchyme harbors the precursors of adult heart-valves. Using a Bmp2 floxed allele and a heart-specific deleter line ( Nkx2.5::Cre ), we showed that Bmp2 is the secreted molecule from myocardium that induces endothelial transformation. Further, Bmp2 is both necessary and sufficient to specify this region to form valves. Next, this dissertation focuses on how the endothelium of the heart-valve forming region transduces the myocardial signal to produce mesenchyme. We analyzed the transcription factor Gata4, which is highly expressed in this region. Using a Gata4 floxed allele and an endothelium-specific deleter line ( Tie2::Cre ) we showed that Gata4 is necessary for formation of heart-valve mesenchyme. We demonstrated that Gata4 is required for expression of Erbb3, which uses a Ras-Erk pathway to promote mesenchyme formation. Analogous human phenotypes suggest that Gata4 mutations underlie a spectrum of heart-valve etiologies.