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UBC Theses and Dissertations

The cell autonomous and cell non-automous roles of YAP1 during pancreatogenesis Wang, Shihao


The HIPPO signaling pathway is highly conserved and affects organ development specifically through cellular differentiation and proliferation. Yes-associated protein 1 (YAP1) is a downstream effector of the HIPPO signaling pathway that controls the transcription of a number of secreted factors and cell-to-cell signalling pathways. Although many downstream targets of YAP1 were known to be secreted factors, the observation that YAP1 acts via cell autonomous and non-cell autonomous mechanisms has only recently been described. Given that an active form of YAP1 has been shown to block differentiation of pancreatic progenitor cells during development, we characterized whether these effects involved cell autonomous or cell non-autonomous signalling. To understand the cell autonomous and cell non-autonomous function of YAP1, we utilized loss and gain of function approaches and lineage tracing tools to examine the role of YAP1 during progenitor cell differentiation, as well as its potential impact on other cell types in the pancreas. Our animal model allowed us to manipulate the pancreatic progenitor cells in a mosaic manner. I found that maintaining YAP1 activation cell autonomously blocks the differentiation of both bipotent progenitor and acinar progenitor cells during pancreas development. I also found that progenitor cells not expressing active YAP1 non-cell autonomously acquired the acinar and endocrine cells fate. We also examined functionally whether YAP1-expressing bipotent progenitor and acinar progenitor cells could differentiate outside their normal differentiation window. In addition, our data indicated that YAP1 activity in pancreatic progenitor cells non-cell autonomously regulated the mesenchymal population and the remodeling of the vascular system. These findings revealed a cell autonomous and non-cell autonomous function of YAP1 in the developing pancreatic epithelium and uncovered a YAP1-mediated three-way regulatory interaction between progenitor epithelium, mesenchyme and the vasculature during pancreas development.

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