In this publication, dedicated to Professor Robert H. Anderson and his contributions to the field of cardiac development, anatomy, and congenital heart disease, we will review some of our earlier collaborative studies. The focus of this paper is on our work on the development of the atrioventricular mesenchymal complex, studies in which Professor Anderson has played a significant role. We will revisit a number of events relevant to atrial and atrioventricular septation and present new data on the development of the mesenchymal cap of the atrial septum, a component of the atrioventricular mesenchymal complex which, thus far, has received only moderate attention.

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This paper is dedicated to the memory of Dr. Adriana “Adri” Gittenberger-de Groot and in appreciation of her work in the field of developmental cardiovascular biology and the legacy that she has left behind. During her impressive career, Dr. Gittenberger-de Groot studied many aspects of heart development, including aspects of cardiac valve formation and disease and the role of the epicardium in the formation of the heart. In this contribution, we review some of the work on the role of epicardially-derived cells (EPDCs) in the development of the atrioventricular valves and their potential involvement in the pathogenesis of myxomatous valve disease (MVD). We provide an overview of critical events in the development of the atrioventricular junction, discuss the role of the epicardium in these events, and illustrate how interfering with molecular mechanisms that are involved in the epicardial-dependent formation of the atrioventricular junction leads to a number of abnormalities. These abnormalities include defects of the AV valves that resemble those observed in humans that suffer from MVD. The studies demonstrate the importance of the epicardium for the proper formation and maturation of the AV valves and show that the possibility of epicardial-associated developmental defects should be taken into consideration when determining the genetic origin and pathogenesis of MVD.