Abstract
Mutations in either of two tumor suppressor genes, TSC1 or TSC2, cause tuberous sclerosis complex (TSC), a syndrome resulting in benign hamartomatous tumors and neurological disorders. Cellular growth defects and neuronal disorganization associated with TSC are believed to be due to upregulated TOR signaling. We overexpressed Rheb, an upstream regulator of TOR, in two different subsets of D. melanogaster central brain neurons in order to upregulate the Tsc-Rheb-TOR pathway. Overexpression of Rheb in either the mushroom bodies or the insulin producing cells resulted in enlarged axon projections and cell bodies, which continued to increase in size with prolonged Rheb expression as the animals aged. Additionally, Rheb overexpression in the mushroom bodies resulted in deficiencies in 3 hr but not immediate appetitive memory. Thus, Rheb overexpression in the central brain neurons of flies causes not only morphological phenotypes, but behavioral and aging phenotypes that may mirror symptoms of TSC.
Highlights
Tuberous sclerosis complex (TSC) is a multisystem autosomaldominant syndrome caused by mutations inactivating one of two tumor suppressor genes, TSC1 or TSC2
We chose to use Rheb overexpression in the fly nervous system since it has previously been shown to upregulate TOR activity and gives similar phenotypes to Tsc1 null clones [6,20,21,22]; use of RNAi constructs seen to reduce Tsc1 or Tsc2 in other tissues were unsuccessful in these two neuronal subsets, presumably due to the resistance of the Drosophila nervous system to RNAi [26]
OK107-Gal4 drives UAS transgene expression in the insulin producing cells (IPCs), a set of neurosecretory cells located along the midline of the brain (Fig. 1A, arrowhead), as well as at lower levels in a few other neurons within the brain [32,33,34]
Summary
Tuberous sclerosis complex (TSC) is a multisystem autosomaldominant syndrome caused by mutations inactivating one of two tumor suppressor genes, TSC1 or TSC2. It is typified by formation of hamartomas, or benign tumors, in multiple organ systems such as the heart, lungs, kidneys, brain and skin [1] and is commonly connected with a wide array of potentially devastating neurological phenotypes, including intellectual, behavioral and psychiatric disorders. Loss of TSC1 or TSC2 function or experimental overexpression of Rheb results in upregulated TOR activity, as seen both by increased phosphorylated S6K and enhanced cellular growth that can be repressed through administration of rapamycin [6,13,14,15]
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