Epithelial cell polarity

 

In vertebrate embryos cell polarity is reflected in asymmetric division of progenitor cells and in epithelial to mesenchymal transition during developmental processes, such as mesoderm involution during gastrulation or neural crest cell migration. We would like to understand how communication between embryonic cells regulates polarized protein trafficking and cell polarity during early development.


The control of cell polarity by PAR (partitioning defective) proteins was discovered in the C. elegans embryo, yet these proteins are conserved throughout the animal kingdom. The apical Par protein complex, consisting of the PDZ-containing proteins Par-6 and Par-3 and atypical protein kinase C (aPKC), functions to control asymmetric divisions and establish cell polarity in a variety of cell types, especially in epithelial cells. Par-6 associates with aPKC and its substrate, the product of lethal giant larvae (Lgl). Lgl is a WD domain-containing tumor suppressor that is essential for cell polarity determination and formation of adherens junctions in Drosophila. Activation of aPKC in this complex results in phosphorylation of Lgl and its dissociation from the cortex. These observations show that the Par complex regulates epithelial cell polarity through Lgl. Work from different groups including ours has demonstrated that both Lgl and the polarity kinase PAR-1 associate with Dishevelled, an essential mediator of Wnt signaling, and are regulated by Wnt proteins. Our current studies are focused on the elucidation of the mechanism used by Lgl and PAR-1 to control epithelial polarity.


We have discovered that Diversin a putative regulator of noncanonical Wnt signaling and beta-catenin degradation, is localized to the centrosome and is essential for centrosomal and cilia functions (Itoh et al., 2009; Yasunaga et al., 2011; Itoh et al., 2011). The centrosome is essential for the formation of the cilia and has been implicated in cell polarization and signaling during early embryonic development. A number of Wnt pathway components were found to localize at the centrosome, but how this localization relates to their signaling functions is unclear. In this study, we assessed a role for Diversin, a putative Wnt pathway mediator, in developmental processes that involve cilia. We find that Diversin is specifically localized to the basal body compartment near the base of the cilium in Xenopus multi-ciliated skin cells. Overexpression of Diversin RNA disrupted basal body polarization in these cells, suggesting that tightly regulated control of Diversin levels is crucial for this process. In cells depleted of endogenous Diversin, basal body structure appeared abnormal and this was accompanied by disrupted polarity, shortened or absent cilia and defective ciliary flow. These results are consistent with the involvement of Diversin in processes that are related to the acquisition of cell polarity and require ciliary functions. Our group would like to understand how the centrosome is involved in the control of cell polarity and signaling.