Epicardial deletion of Sox9 leads to myxomatous valve degeneration and identifies Cd109 as a novel gene associated with valve development.

Epicardial-derived cells (EPDCs) are involved in the regulation of myocardial growth and coronary vascularization and are critically important for proper development of the atrioventricular (AV) valves. SOX9 is a transcription factor expressed in a variety of epithelial and mesenchymal cells in the developing heart, including EPDCs. To determine the role of SOX9 in epicardial development, an epicardial-specific Sox9 knockout mouse model was generated. Deleting Sox9 from the epicardial cell lineage impairs the ability of EPDCs to invade both the ventricular myocardium and the developing AV valves. After birth, the mitral valves of these mice become myxomatous with associated abnormalities in extracellular matrix organization. This phenotype is reminiscent of that seen in humans with myxomatous mitral valve disease (MVD). An RNA-seq analysis was conducted in an effort to identify genes associated with this myxomatous degeneration. From this experiment, Cd109 was identified as a gene associated with myxomatous valve pathogenesis in this model. Cd109 has never been described in the context of heart development or valve disease. This study highlights the importance of SOX9 in the regulation of epicardial cell invasion-emphasizing the importance of EPDCs in regulating AV valve development and homeostasis-and reports a novel expression profile of Cd109, a gene with previously unknown relevance in heart development.

Sox9 Expression in the Second Heart Field; A Morphological Assessment of the Importance to Cardiac Development with Emphasis on Atrioventricular Septation.

Failure to form the septal structures that separate the left and right cardiac chambers results in defects that allow shunting of blood from one side of the heart to the other, leading to the mixing of oxygenated and de-oxygenated blood. The atrioventricular (AV) mesenchymal complex, consisting of the AV cushions, the Dorsal Mesenchymal Protrusion (DMP), and the mesenchymal cap, plays a crucial role in AV septation. Cells found in these structures derive from different cell lineages. In this study we have investigated the role of the transcription factor Sox9 in the Second Heart Field (SHF) with the emphasis on the formation of the atrioventricular septal complex. Using a mouse model in which Sox9 is conditionally deleted from the SHF we demonstrate that in this model virtually all mouse embryos develop septal abnormalities, including complete atrioventricular septal defects (cAVSDs) and isolated ventricular septal defects. Our morphological analyses indicate that perturbation of the development of the mesenchymal cap appears to play a crucial role in the pathogenesis of the atrial septal defects observed in the AVSDs and suggests that this component of the AV mesenchymal complex might play a more important role in AV septation than previously appreciated.

Role of the Epicardium in the Development of the Atrioventricular Valves and Its Relevance to the Pathogenesis of Myxomatous Valve Disease.

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.

The Mesenchymal Cap of the Atrial Septum and Atrial and Atrioventricular Septation.

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.