Diet and energy-sensing inputs affect TorC1-mediated axon misrouting but not TorC2-directed synapse growth in a Drosophila model of tuberous sclerosis.
The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system.
Department of Genetics, Cell Biology and Development, Developmental Biology Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
Brian
B
Dimitroff
Katie
K
Howe
Adrienne
A
Watson
Bridget
B
Campion
Hyun-Gwan
HG
Lee
Na
N
Zhao
Michael B
MB
O'Connor
Thomas P
TP
Neufeld
Scott B
SB
Selleck
D000818:Animals; D001369:Axons; D004032:Diet; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster; D004734:Energy Metabolism; D009420:Nervous System / Q000254:growth & development; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014402:Tuberous Sclerosis / Q000503:physiopathology*
D029721:Drosophila Proteins; C570998:TORC1 protein complex, Drosophila; D014157:Transcription Factors; D011494:Protein Kinases; C416303:target of rapamycin protein, Drosophila; D058570:TOR Serine-Threonine Kinases