Abstract
The conserved TOR kinase signaling network links nutrient availability to cell, tissue and body growth in animals. One important growth-regulatory target of TOR signaling is ribosome biogenesis. 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 we show in Drosophila larvae that ribosome synthesis in muscle is required non-autonomously to maintain normal body growth and development. We find that amino acid starvation and TOR inhibition lead to reduced levels of TIF-IA, and decreased rRNA synthesis in larval muscle. When we mimic this decrease in muscle ribosome synthesis using RNAi-mediated knockdown of TIF-IA, we observe delayed larval development and reduced body growth. This reduction in growth is caused by lowered systemic insulin signaling via two endocrine responses: reduced expression of Drosophila insulin-like peptides (dILPs) from the brain and increased expression of Imp-L2—a secreted factor that binds and inhibits dILP activity—from muscle. We also observed that maintaining TIF-IA levels in muscle could partially reverse the starvation-mediated suppression of systemic insulin signaling. Finally, we show that activation of TOR specifically in muscle can increase overall body size and this effect requires TIF-IA function. These data suggest that muscle ribosome synthesis functions as a nutrient-dependent checkpoint for overall body growth: in nutrient rich conditions, TOR is required to maintain levels of TIF-IA and ribosome synthesis to promote high levels of systemic insulin, but under conditions of starvation stress, reduced muscle ribosome synthesis triggers an endocrine response that limits systemic insulin signaling to restrict growth and maintain homeostasis.
Highlights
Nutrient availability is a critical determinant of cell, tissue and body growth in developing animals
We use Drosophila larvae to identify a role for ribosome synthesis—a key metabolic process—in mediating nutrient and TOR effects on body growth
We find that inhibition of muscle ribosome synthesis leads to reduced systemic insulin-like growth factor signaling via two endocrine responses—decreased expression of brain derived Drosophila insulin-like peptides and increased expression of Imaginal morphogenesis protein-L2 (Imp-L2), an inhibitor of insulin signaling
Summary
Nutrient availability is a critical determinant of cell, tissue and body growth in developing animals. Two decades of research has identified the Target-of-Rapamycin (TOR) kinase signaling pathway as a major nutrient-responsive growth pathway in eukaryotes [1,2]. TOR functions in two distinct complexes – TORC1 and TORC2 – and it is TOR kinase activity within TORC1 that has been established as a growth driver. A complex intracellular signaling network activates TOR kinase activity within TORC1 in response to availability of extracellular nutrients such as amino acids and glucose. TORC1, in turn, stimulates many cell metabolic processes that drive growth and proliferation [2,3]. When nutrients are limiting, TORC1 activity is inhibited and cells switch their metabolism to promote homeostasis and survival during starvation conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
