Editors' ChoiceNeuroscience

Limiting mTOR to Properly Limit Neurons

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Sci. Signal.  16 Feb 2010:
Vol. 3, Issue 109, pp. ec55
DOI: 10.1126/scisignal.3109ec55

Early in development, neurons send out many axonal projections, some of which are guided to their proper destination and some of which are removed. Tuberous sclerosis complex (TSC) is an autosomal-dominant disease characterized by benign tumors and neurological disorders, such as epilepsy and autism. TSC is caused by mutations in either the TSC1 or TSC2 gene, the products of which form a complex that inhibits mammalian target of rapamycin (mTOR) signaling. Nie et al. report that loss of heterozygosity in Tsc2 in mice (Tsc2+/–) caused increased mTOR activity in axons, resulting in excessive numbers of axonal projections. Retinal ganglion cells (RGCs) from wild-type mice had increased mTOR activity [increased phosphorylation of Tsc2 at an inhibitory site, increased abundance of Rheb, and increased phosphorylation of ribosomal S6 kinase 1 (S6K1) at an activating site] in their axons, compared with that in their dendrites. RGCs from Tsc2+/– mice showed increased active S6K1 compared with those from wild-type mice, confirming that heterozygous Tsc2 mice have increased mTOR activity. The authors labeled RGCs with dye to follow their projections into the dorsal lateral geniculate nucleus of the brain and found that the Tsc2+/– mice had excessive projections, a phenotype similar to that of ephrinA-knockout mice. Isolated RGCs from Tsc2+/– mice showed reduced ephrinA1-induced growth cone collapse. Cortical neurons cultured from wild-type mice responded to ephrinA1 with dephosphorylation of extracellular signal–regulated kinases 1 and 2 (ERK1/2) (decreased activity), decreased S6K1 phosphorylation (decreased activity), and no change in Akt phosphorylation. EphrinA1 also inhibited translation in growth cones of cultured rat hippocampal neurons. ERK1/2 phosphorylates and inactivates Tsc2. Treatment of cortical neurons with ephrinA1 decreased the phosphorylation of Tsc2 at the ERK1/2 site (thus increasing Tsc2 activity and decreasing mTOR activity). Thus, ephrinA1-mediated inhibition of axonal translation requires a functional TSC1/2 complex and contributes to growth cone collapse and proper axonal connectivity.

D. Nie, A. Di Nardo, J. M. Han, H. Baharanyi, I. Kramvis, T. Huynh, S. Dabora, S. Codeluppi, P. P. Pandolfi, E. B. Pasquale, M. Sahin, Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat. Neurosci. 13, 163–172 (2010). [PubMed]

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