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Tsc2-Rheb signaling regulates EphA-mediated axon guidance. | LitMetric

Tsc2-Rheb signaling regulates EphA-mediated axon guidance.

Nat Neurosci

The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

Published: February 2010

AI Article Synopsis

  • - Tuberous sclerosis complex results from mutations in TSC1 or TSC2 genes, disrupting the regulation of the mTOR signaling pathway, which is linked to benign tumors and unknown neurological symptoms.
  • - In studies with mice, a decrease in Tsc2 led to irregular visual nerve projections, hinting at issues with how nerve cells guide their axons.
  • - The research shows that ephrin stimulation can enhance Tsc2 activity and inhibit mTOR, suggesting that both the TSC2-Rheb-mTOR pathway and ephrin-Eph receptor interactions are crucial for proper axon guidance in the visual system.

Article Abstract

Tuberous sclerosis complex is a disease caused by mutations in the TSC1 or TSC2 genes, which encode a protein complex that inhibits mTOR kinase signaling by inactivating the Rheb GTPase. Activation of mTOR promotes the formation of benign tumors in various organs and the mechanisms underlying the neurological symptoms of the disease remain largely unknown. We found that Tsc2 haploinsufficiency in mice caused aberrant retinogeniculate projections that suggest defects in EphA receptor-dependent axon guidance. We also found that EphA receptor activation by ephrin-A ligands in neurons led to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity and decreased inhibition of Tsc2 by ERK1/2. Thus, ephrin stimulation inactivates the mTOR pathway by enhancing Tsc2 activity. Furthermore, Tsc2 deficiency and hyperactive Rheb constitutively activated mTOR and inhibited ephrin-induced growth cone collapse. Our results indicate that TSC2-Rheb-mTOR signaling cooperates with the ephrin-Eph receptor system to control axon guidance in the visual system.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812631PMC
http://dx.doi.org/10.1038/nn.2477DOI Listing

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