Regulation of Epithelial Proliferation and Migration by Apical-Basal Polarity Proteins

Epithelial cells line all the outside surfaces of the body where they perform essential roles in maintaining homeostasis. In addition, epithelial tissues are implicated in many disease processes and are the most common tissue type to give rise to human cancer. Therefore, a thorough understanding of epithelial development and homeostasis has broad implications for understanding human development, health, and disease. The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Proper apical-basal polarity (ABP) is required for epithelial tissues to carry out their functions, which include absorption, secretion, barrier formation, and collective migration. ABP proteins are also tumor suppressors that are targeted for disruption by oncogenic viruses and are commonly mutated in human carcinomas. Disruption of these ABP proteins is an early event in cancer development that results in increased proliferation and epithelial disorganization through means not fully characterized. Using the Drosophila melanogaster wing disc epithelium, we first demonstrate that disruption of apical vs. basolateral polarity results in increased proliferation via distinct downstream signaling pathways. Surprisingly, the Rho-Rok-Myosin contractility apparatus appears to play opposite roles in the regulation of this proliferative phenotype based on which polarity complex is disrupted. In contrast, non-autonomous TNF signaling appears to suppress the proliferation that results from apical-basal polarity disruption, regardless of which complex is disrupted. We also demonstrate that collective migration in the D. melanogaster ovariole follicular epithelium is disrupted in distinct ways depending on whether the apical or basolateral polarity complex is compromised. Using quantitative optical flow image analysis, we show that disruption of the apical polarity complex results in the formation of large holes in the migrating epithelial sheet while maintaining the coordinated movement of collective migration. On the other hand, following disruption of the basolateral complex, epithelial integrity is largely maintained, but the organization of collective motion decreases. Disruption of the ABP signaling network also leads to increased epithelial proliferation via the action of Ajuba LIM family of adaptor molecules on the Hippo pathway. We show that the Ajuba LIM proteins specifically inhibit the Hippo core kinases by sequestering these proteins in a cytosolic complex, thereby allowing the downstream transcriptional co-activator YAP, to migrate to the nucleus and activate transcription of YAP-dependent target genes. These findings provide further insight into how disruption of epithelial polarity complexes can alter cell proliferation and migration during early carcinoma development