Nutrition-dependent control of Ribosome Synthesis and Growth in Drosophila

Abstract

The conserved TOR signaling pathway links nutrient availability to cell, tissue and body growth in animals. One important downstream growth-regulatory effector of TOR is ribosome synthesis. Studies in yeast and mammalian cell culture have described how TOR controls rRNA synthesis - a limiting step in ribosome biogenesis - via the RNA Polymerase I transcription factor TIF-IA. However, the contribution of TOR-dependent ribosome synthesis to tissue and body growth in animals is less clear. Here I showed in Drosophila larvae that ribosome synthesis in muscle is required nonautonomously to maintain normal body growth and development. In addition, I found that amino acid starvation and TOR inhibition lead to reduced TIF-IA levels and decreased rRNA synthesis in the larval muscle. When I mimicked this decrease in muscle ribosome synthesis using RNAi-mediated knockdown of TIF-IA, I found delayed larval development and reduced body growth. This reduction in growth is caused by reduced systemic insulin signaling via two endocrine responses: First, reduced expression and release of Drosophila insulin-like peptides (dILPs) from the brain. Second, increased expression of Imp-L2 - a secreted factor, which binds and inhibits dILP activity from muscle. I also observed that maintaining TIF-IA levels in muscle could partially reverse the starvation-mediated inhibition of systemic insulin signaling. Finally, I showed that activation of TOR specifically in muscle can increase overall body size and this effect requires TIF-IA function. In contrast to muscle tissue, inhibition of ribosome synthesis in fat body modestly delayed development and had no effects on body growth. Moreover, the effect of ribosome synthesis inhibition in the fat body on developmental timing and body growth had weak effects on suppression of systemic insulin signaling. Overall, my data suggest that muscle ribosome synthesis functions as a nutrient-dependent checkpoint for overall body growth. Upon nutrient availability, TOR is required to maintain levels of TIF-IA and ribosome synthesis to keep high levels of systemic insulin. Conversely, upon starvation, muscle ribosome synthesis is reduced and triggers an endocrine response that limits systemic insulin signaling to restrict growth and maintain homeostasis.