Tuberous sclerosis complex regulates Drosophila neuromuscular junction growth via the TORC2/Akt pathway.

Mutations in the tuberous sclerosis complex (TSC) are associated with various forms of neurodevelopmental disorders, including autism and epilepsy. The heterodimeric TSC complex, consisting of Tsc1 and Tsc2 proteins, regulates the activity of the TOR (target of rapamycin) complex via Rheb, a small GTPase. TOR, an atypical serine/threonine kinase, forms two distinct complexes TORC1 and TORC2. Raptor and Rictor serve as specific functional components of TORC1 and TORC2, respectively. Previous studies have identified Tsc1 as a regulator of hippocampal neuronal morphology and function via the TOR pathway, but it is unclear whether this is mediated via TORC1 or TORC2. In a genetic screen for aberrant synaptic growth at the neuromuscular junctions (NMJs) in Drosophila, we identified that Tsc2 mutants showed increased synaptic growth. Increased synaptic growth was also observed in rictor mutants, while raptor knockdown did not phenocopy the TSC mutant phenotype, suggesting that a novel role exists for TORC2 in regulating synapse growth. Furthermore, Tsc2 mutants showed a dramatic decrease in the levels of phosphorylated Akt, and interestingly, Akt mutants phenocopied Tsc2 mutants, leading to the hypothesis that Tsc2 and Akt might work via the same genetic pathway to regulate synapse growth. Indeed, transheterozygous analysis of Tsc2 and Akt mutants confirmed this hypothesis. Finally, our data also suggest that while overexpression of rheb results in aberrant synaptic overgrowth, the overgrowth might be independent of TORC2. Thus, we propose that at the Drosophila NMJ, TSC regulates synaptic growth via the TORC2-Akt pathway.