Effects of Mechanical Signaling Through YAP During Early Branching Morphogenesis in Mouse Lungs

Abstract

This thesis proposes a model for the effects of YAP signaling on Sox2 and Sox9 expression and lung morphology during the E12 stage of branching morphogenesis in mouse lungs. Results of culturing experiments demonstrate that inhibiting YAP causes growth of the epithelium into cystic structures rather than distinct branches. Results of immunostaining experiments suggest that YAP constrains Sox2 and Sox9 to the airway epithelium, and that inhibiting YAP allows expansion of Sox2 and Sox9 expression into the mesenchyme, which leads to abnormal branching morphogenesis. Results of qPCR experiments provide quantitative confirmation that YAP inhibition causes additional expression of Sox2 and Sox9. Together, these results suggest that normal branching morphogenesis requires the absence of Sox2 and Sox9 expression in the mesenchyme to promote smooth muscle wrapping. Future research should examine YAP signaling at stages of development before and after E12, study different downstream proteins of the YAP signaling pathway, and use other experimental techniques to separately quantify protein expression in the epithelium and in the mesenchyme. This research has important implications for engineering of complex branched lung tissues to treat lung diseases.