Mechanisms of TSC-mediated control of synapse assembly and axon guidance.
Tuberous sclerosis complex is a dominant genetic disorder produced by mutations in either of two tumor suppressor genes, TSC1 and TSC2; it is characterized by hamartomatous tumors, and is associated with severe neurological and behavioral disturbances. Mutations in TSC1 or TSC2 deregulate a conserved growth control pathway that includes Ras homolog enriched in brain (Rheb) and Target of Rapamycin (TOR). To understand the function of this pathway in neural development, we have examined the contributions of multiple components of this pathway in both neuromuscular junction assembly and photoreceptor axon guidance in Drosophila. Expression of Rheb in the motoneuron, but not the muscle of the larval neuromuscular junction produced synaptic overgrowth and enhanced synaptic function, while reductions in Rheb function compromised synapse development. Synapse growth produced by Rheb is insensitive to rapamycin, an inhibitor of Tor complex 1, and requires wishful thinking, a bone morphogenetic protein receptor critical for functional synapse expansion. In the visual system, loss of Tsc1 in the developing retina disrupted axon guidance independently of cellular growth. Inhibiting Tor complex 1 with rapamycin or eliminating the Tor complex 1 effector, S6 kinase (S6k), did not rescue axon guidance abnormalities of Tsc1 mosaics, while reductions in Tor function suppressed those phenotypes. These findings show that Tsc-mediated control of axon guidance and synapse assembly occurs via growth-independent signaling mechanisms, and suggest that Tor complex 2, a regulator of actin organization, is critical in these aspects of neuronal development.
Knox
Sarah
S
The Developmental Biology Center, Department of Pediatrics, The University of Minnesota, Minneapolis, Minnesota, United States of America.
Ge
Hong
H
Dimitroff
Brian D
BD
Ren
Yi
Y
Howe
Katie A
KA
Arsham
Andrew M
AM
Easterday
Mathew C
MC
Neufeld
Thomas P
TP
O'Connor
Michael B
MB
Selleck
Scott B
SB
D000818:Animals; D001369:Axons; D018797:Cell Cycle Proteins / Q000502:physiology*; D029721:Drosophila Proteins / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects
D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C515347:TSC1 protein, Drosophila; C117726:gig protein, Drosophila; D020123:Sirolimus