Two-tiered control of epithelial growth and autophagy by the insulin receptor and the Ret-like receptor, Stitcher. Fergal O'Farrell^1,2, Shenqiu Wang², Christos Samakovlis², Tor Erik Rusten¹. 1) Dept. of Biochemistry, Institute for Cancer Research The Norwegian Radium Hospital Oslo, Norway; 2) Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

   Body size in Drosophila larvae, like in other animals, is controlled by nutrition. Nutrient restriction leads to catabolic responses in the majority of tissues but the Drosophila mitotic imaginal discs continue growing. The nature of these differential control mechanisms that sparing spare distinct tissues from starvation are poorly understood. Here, we reveal that the Ret-like receptor tyrosine kinase (RTK), Stitcher (Stit) is required for cell growth and proliferation through the PI3K-I/TORC1 pathway in the Drosophila wing disc. Both Stit and insulin receptor (InR) signalling activate PI3K-I and drive cellular proliferation and tissue growth. However, whereas optimal growth requires signalling from both InR and Stit, catabolic changes manifested by autophagy only occur when both signalling pathways are compromised. This was determined using RNAi, dominant negative and stit FRT mutant reagents to inactivate Stit either compartmentally or in clones in the wing followed by quantification of mitotic (BrdU/PH3/CycB), growth (TORC1 targets S6K/4E-BP), autophagic (Atg8a) and PI3K-I signalling read-outs in addition to effects upon cell numbers at larval, pupal and adult stages. This was complemented with overexpression studies in the larval fat body. The combined activities of Stit and InR in ectodermal epithelial tissues provide an RTK-mediated, two-tiered reaction threshold to varying nutritional conditions that promotes epithelial organ growth even at low levels of InR signalling.