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Tsc2-Rheb signaling regulates EphA-mediated axon guidance.

Nature neuroscience | Feb 27, 2010

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.

Pubmed ID: 20062052 RIS Download

Mesh terms: Animals | Axons | Brain-Derived Neurotrophic Factor | Cell Movement | Cells, Cultured | Ephrin-A1 | Growth Cones | Intracellular Signaling Peptides and Proteins | Mice | Mice, Transgenic | Mitogen-Activated Protein Kinase 1 | Mitogen-Activated Protein Kinase 3 | Monomeric GTP-Binding Proteins | Neurons | Neuropeptides | Protein-Serine-Threonine Kinases | Rats | Receptors, Eph Family | Retina | Retinal Ganglion Cells | Signal Transduction | TOR Serine-Threonine Kinases | Tumor Suppressor Proteins | Visual Pathways

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Associated grants

  • Agency: NICHD NIH HHS, Id: P01 HD18655
  • Agency: NICHD NIH HHS, Id: P30 HD018655
  • Agency: NINDS NIH HHS, Id: NS58956
  • Agency: Howard Hughes Medical Institute, Id: HD025938
  • Agency: NICHD NIH HHS, Id: R01 NS058956
  • Agency: NINDS NIH HHS, Id: P01 HD025938
  • Agency: NICHD NIH HHS, Id: R01 NS058956-01
  • Agency: NINDS NIH HHS, Id:

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