Nutrition/TOR signaling promotes growth via the conserved Pol I transcription factor, TIF-IA in Drosophila. Abhishek Ghosh, Savraj S. Grewal. Clark H. Smith Brain Tumor Centre, SACRI, University of Calgary, Calgary, AB, T2N 4N1, Canada.

   The conserved Target of Rapamycin (TOR) kinase signaling pathway links nutrition to growth in Drosophila. The upstream components of the TOR pathway are known. In contrast, the downstream effectors via which TOR promotes growth are less clear. We are exploring the role of ribosomal RNA (rRNA) synthesis as a growth regulatory target of the nutrition/TOR pathway in Drosophila. Studies in yeast, Drosophila and cultured cells showed that the conserved RNA polymerase I (Pol I) transcription factor TIF-IA links nutrition/TOR to rRNA synthesis. We have found that amino acid starvation leads to reduced TIF-IA transcript and protein levels in Drosophila larvae. These effects of starvation on TIF-IA levels are phenocopied in tor null larvae, but not in S6 kinase (a known TOR effector) mutant larvae. These results suggest that TOR promotes rRNA synthesis via controlling TIF-IA gene expression. Currently, we are investigating how TOR stimulates TIF-IA transcription. In addition to cell autonomous growth, TOR activity in specific tissues such as fat and muscle is promotes systemic growth. For example, in Drosophila, TOR activity is required in the fat body (adipose tissue) to trigger an endocrine response leading to the release of Drosophila insulin like peptides (dILPs) from brain. These dILPs circulate and promote growth in peripheral tissues via the PI3K/Akt signaling pathway. We have found that genetic knockdown of TIF-IA in either fat or muscle leads to reduced larval growth and delayed development, phenocopying loss of TOR. In addition, fat and muscle specific TIF-IA knockdown larvae have altered expression of brain-derived dILPs and Foxo target genes, consistent with reduced systemic insulin signaling. These data suggest that TIF-IA activity and hence, ribosome synthesis may be required for the non-autonomous, endocrine effects of TOR signaling. Overall, this study highlights the role of TIF-IA as a key effector of TOR signaling in the control of tissue and organismal growth.