Analysis of Integrator 1 function in Drosophila epithelial cells. Timm Haack, Dan T. Bergstralh, Daniel St Johnston. The Gurdon Institute and the Department of Genetics, University of Cambridge, Cambridge, United Kingdom.

   We use the follicle cell epithelium of the Drosophila egg chamber to study how epithelial cells establish and maintain polarization. In a forward genetic clonal screen for genes disrupting epithelial polarity and organization we identified a nonsense mutant allele of the conserved Integrator 1 (IntS1) gene called IntS1^1-D15. Cells homozygous for IntS1^1-D15 leave the epithelial monolayer basally and form small wedge-shaped clusters with ectopic apical domains. This behavior of IntS1^1-D15 mutant cells is accompanied by a marked change in cytoskeletal organization characterized by increased microtubules and cortical actin. Mutant clones within the monolayer show altered cell shapes often with constricted apical membranes and partial mixing of apical and lateral membrane markers. IntS1^1-D15 also promotes changes in cell signaling that affect the cell cycle. Wildtype follicle cells switch from mitotic cycling to endocycling during mid-oogenesis in response to Notch signaling. In contrast, mutant IntS1^1-D15 clones in young egg chambers show premature loss of centrosomes and early expression of the transcription factor Hindsight indicating a deregulation of the Notch pathway. The IntS1 protein is part of the Integrator Complex, a large nuclear protein complex that has been linked to snRNA maturation. We aim to investigate whether the change in epithelial cell behavior in IntS1 mutants is a pleiotropic effect due to impaired spliceosomal activity as a consequence of snRNA misprocessing or whether it presents an unknown function of IntS1 independent of snRNA maturation.