Determining the Role of Myrf in the Lung Mesothelium

项目总结/摘要 间皮细胞是中胚层来源的上皮细胞的单层， 包括肺在内的内脏它的作用是防止内部器官相互滑动时产生摩擦 其他和体壁。它是否在发育和体内平衡中发挥其他作用尚不清楚。在 本研究将通过探讨转录因子Myrf的作用来研究间皮功能 在发育过程中在包括肺在内的各种器官的间皮中表达的基因。我走近 Myrf基因的变异已经在先天性腹股沟疝（CDH）中被发现， 与肺发育不全和肺动脉高压相关的缺陷。我已经发现，Myrf的失活， 肺发育的开始导致显著的CDH表型，伴有肺发育不全 在隔膜关闭之前。Fgf 9是一种在间皮中表达的关键生长因子， 减少，这表明Myrf在间皮瘤中的功能是控制间皮瘤功能，作为一种来源， 信号.相比之下，Myrf在分枝阶段的失活导致了Myrf的扩增。 间皮细胞分化成多层细胞。这是惊人的回忆表型时，河马途径 激酶基因Lats 1/2在心外膜中失活，心外膜是心脏中的间皮膜等效细胞层。 与Hippo通路的参与一致，发现下游转录效应子雅普 在Myrf突变体中过量间皮细胞的细胞核中增加。这些发现促使我提出 在发育过程中，Myrf通过调节生长信号的表达来控制间皮功能， (Aim 1）和Hippo-YAP信号通路的组分（Aim 2）。因为肺发育不全是 CDH患者的死亡原因，我的研究结果将促进我们对CDH发病机制的认识。

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.