Disruptions in cell polarity and cell morphology often lead to the disorganization of normal tissue architecture - a characteristic hallmark seen in the early development of epithelial cancers. Recently, our lab identified ZYG11A as a novel regulator of mammalian epithelial cell morphology. Although a role for ZYG11A and the other highly conserved ZYG11 family members, ZYG11B and ZER1, has been described in cell cycle control and HPV16 E7 viral oncoprotein function, little is known about how these genes contribute to the regulation of cell polarity and morphology.
To investigate the function of ZYG11 family members in epithelial development and cellular organization, I have used a combination of gene expression, live-cell imaging, and high throughput functional genomic analysis in mammalian epithelial cells and have also generated ZYG11 homologue mutants in Drosophila and zebrafish. Our studies provide evidence for divergent functions for individual ZYG11 family members in cell morphology and cell viability, as well as a fundamental requirement for ZYG11 in Drosophila and zebrafish development.
As ZYG11A has also been implicated in protein ubiquitination, it is likely to affect the turnover of a large network of proteins. Using RNAi screening of candidate biochemical and genetic interactors, I have identified key adhesion and polarity proteins as potential targets of ZYG11A regulation. To complement this genetic screen the implementation of proximity-dependent biotin labelling will build a better understanding of the ubiquitination targets and pathways controlled by the ZYG11 family that contribute to the maintenance of cell polarity and morphology, and how this may ultimately regulate the initiation and progression of epithelial cancers.