Diet and Energy-Sensing Inputs Affect TorC1-Mediated Axon Misrouting but Not TorC2-Directed Synapse Growth in a Drosophila Model of Tuberous Sclerosis

Abstract

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.

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…24) and an insertion of an empty pUASTattB vector into the attP landing site at 51C 50 . Pdf-gal4, tim-Gal4:62, 67, 27, repo-gal4 and elav-gal4 have been described previously 24,[51][52][53] . To record period-luciferase rhythms 8.0-luc:9, XLG-luc:1 (ref.…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…Drosophila neuromuscular junction (NMJ) was used to determine the role of TSC complex-Rheb-mTORC1 signaling on synapse assembly and function (Knox et al, 2007;Dimitroff et al, 2012;Natarajan et al, 2013). S6K regulated overall synapse growth (synapse bouton size, active zone number, and density) but not synaptic enlargement measured by the number of synaptic boutons per muscle area (Cheng et al, 2011a).…”

“…Animals bearing mutations in the wishful thinking gene show a very small NMJ with dramatically compromised synaptic function (Knox et al, 2007). The synaptic enlargement by over-expression of Rheb at the NMJ results in altering the balance between the number of synaptic boutons and the size of the underlying muscle which disrupts the normal growth and development (Dimitroff et al, 2012).…”

“…Axon targeting has been studied extensively using the Drosophila visual system (Tayler and Garrity, 2003;Knox et al, 2007;Dimitroff et al, 2012). A study on the role of Rheb in the mushroom bodies of Drosophila shows that over-expression of Rheb in the mushroom bodies results in enlarged axonal lobes (Brown et al, 2012).…”

“…A study on the role of Rheb in the mushroom bodies of Drosophila shows that over-expression of Rheb in the mushroom bodies results in enlarged axonal lobes (Brown et al, 2012). Rheb overexpression produced cell autonomous defects in photoreceptor axon guidance in the Drosophila visual system, but did not produce motor-neuron axon misrouting and the motor-neuron axon follows the normal trajectory and synapses at the correct location on muscle (Knox et al, 2007;Dimitroff et al, 2012).…”