Screen Reveals Novel Roles for Tau, and Morphogen Gradients in Resolving an Epithelial Identity Crisis

Abstract

Epithelia, surrounding our organs and bodies, form the first line of defence against environmental insults such as wounding and infection. A constant cell turnover is essential for the renewal and integrity of the epithelium. The high turnover leads to high frequency of mistakes, and makes epithelial cancers, termed carcinomas, the most prominent cancer type. Hence, epithelial turnover and homeostasis need to be strictly controlled. The developing Drosophila wing consists of a two-layered epithelium and constitutes one of the best model organs to study epithelial development and homeostasis. Here, we describe our three-tiered screening efforts that led to the identification of new players in epithelial maintenance. Selector genes act as location identity cards during development, and cells expressing the wrong selector genes for a specific location are eliminated from the epithelium. We experimentally modulate levels of Apterous, the dorsal identity gene, in cell clones, to generate cells destined to be eliminated. We isolated such cells along with their immediate neighbours with laser microdissection and determined differentially expressed genes compared to control patches. We screened these candidate genes for their ability to influence elimination of aberrant cells using RNA interference, identifying five proteins with novel roles in epithelial homeostasis: Tau, a neuronal protein, Shifted, a modulator of morphogen gradients, Wnt oncogene analog 4, p-element induced wimpy testis, which silences transposons and CG5567, a phosphatase predicted to be involved in glycerol biosynthesis. The next step will be to delineate their roles in the recognition and elimination of harmful cells.