Determining the Role of Myrf in the Lung Mesothelium

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PROJECT SUMMARY/ABSTRACT The mesothelium is a monolayer of mesoderm-derived epithelial cells that encapsulates many of our internal organs, including the lung. Its ascribed role is to prevent friction as internal organs slide against each other and the body wall. Whether it plays other roles in development and homeostasis is poorly understood. In this study, I will investigate mesothelium function through interrogating the role of Myrf, a transcription factor gene expressed in the mesothelium of various organs, including the lung during development. I approached Myrf because variants in this gene have been identified in congenital diaphragmatic hernia (CDH), a birth defect associated with lung hypoplasia and pulmonary hypertension. I have found that inactivation of Myrf at the start of lung development resulted in a striking CDH phenotype accompanied by pulmonary hypoplasia prior to diaphragm closure. The expression of Fgf9, a key growth factor expressed in the mesothelium is reduced, suggesting that Myrf function in the mesothelium is to control mesothelium function as a source of signals. In comparison, inactivation of Myrf later on at the branching stage resulted in the expansion of the mesothelium into multiple cell layers. This is strikingly reminiscent of the phenotype when Hippo pathway kinase genes Lats 1/2 were inactivated in the epicardium, a mesothelium-equivalent cell layer in the heart. Consistent with an involvement of Hippo pathway, YAP, a downstream transcription effector, was found increased in the nucleus of the excess mesothelial cells in the Myrf mutant. These findings led me to propose that during development, Myrf controls mesothelium function by regulating the expression of growth signals (Aim 1) and components of the Hippo-YAP signaling pathway (Aim 2). Since pulmonary hypoplasia is a key cause of mortality in CDH patients, my findings will advance our knowledge on CDH disease mechanism.