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.

心外膜源性细胞 (EPDC) 参与心肌生长和冠状血管形成的调节，对于房室 (AV) 瓣膜的正常发育至关重要。SOX9 是一种转录因子，在发育中的心脏的多种上皮细胞和间充质细胞（包括 EPDC）中表达。为了确定 SOX9 在心外膜发育中的作用，建立了心外膜特异性Sox9敲除小鼠模型。从心外膜细胞谱系中删除Sox9会损害 EPDC 侵入心室心肌和发育中的房室瓣膜的能力。出生后，这些小鼠的二尖瓣变得粘液瘤，并伴有细胞外基质组织的异常。这种表型让人想起患有粘液瘤性二尖瓣疾病 (MVD) 的人类。为了鉴定与这种粘液瘤变性相关的基因，进行了 RNA 测序分析。从该实验中，Cd109被鉴定为与该模型中粘液瘤性瓣膜发病机制相关的基因。从未在心脏发育或瓣膜疾病的背景下描述过Cd109 。这项研究强调了 SOX9 在调节心外膜细胞侵袭中的重要性，强调了 EPDC 在调节 AV 瓣膜发育和稳态中的重要性，并报告了Cd109的新表达谱，这是一种以前未知的与心脏发育相关的基因。