The polarization of epithelial cells is essential for the integrity and function of most tissues and organs, and defective epithelial polarity is associated with a broad range of diseases, including more than 90% of cancers. Maturation of epithelial polarity correlates with cell differentiation during development. However, whether polarity controls cell fate signals and how deregulated polarity is linked to disease progression is still poorly understood. The long term OBJECTIVE of our work is to gain much needed mechanistic insight into the cues bridging epithelial cell polarity and cell fate, and to understand how deregulation of these signals drives defects in the developing and adult respiratory system. There are three evolutionarily conserved protein complexes that govern apical-basal epithelial polarity: the Crumbs, Par and Scribble complexes. Our HYPOTHESIS is that the apical-basal dynamics of these polarity complexes directs intracellular signals required for specifying cell fat in the respiratory epithelium. Our prior and preliminary studies demonstrate that the Crumbs family member, Crb3, and the polarity-regulated Par1b kinase mediate the localization and activity of the transcriptional regulator YAP. YAP is a key effector of the Hippo signaling pathway that has vital roles controlling cell proliferation, survival and cell fate. Our preliminar work indicates that the nuclear-cytoplasmic dynamics of YAP localization directs cell fate specification in the developing and adult respiratory epithelium of the mouse, and that YAP localization is regulated by the apical-basal dynamics of Crb3 and Par1b. We have uncovered a novel Par1b-induced posttranslational modification that directs YAP activity, providing a direct mechanism for how polarity proteins control YAP localization, and ultimately how polarity may govern cell fate.
Our AIMS are to: 1) dissect the relationship between Par1b and YAP, and define how this affects respiratory epithelial progenitor cell fate;and 2) determine how the apica determinant Crb3 controls YAP localization and assess how the loss of Crb3 affects respiratory epithelial development and homeostasis. Taken together, our studies will provide insight in the mechanisms directing epithelial organization and define crucial signals linked to the onset of diseases, such as cancer. As such, we anticipate our work will generate promising leads for epithelial-related diseases, and will provide a framework for understanding fundamental developmental events.
The asymmetric architecture of a cell (known as cell polarity) is disrupted in a wide range of devastating diseases, many of which have no effective treatments. Very little is known about cell polarity-associated cues, and thus given their broad impact in development and disease comprehending such signals is a clear research priority. Insight gained from our proposed work will provide key molecular knowledge required to understand cell polarity-associated diseases, offering novel therapeutic targets and strategies.