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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axons / physiology*
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Brain-Derived Neurotrophic Factor / metabolism
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Cell Movement / physiology*
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Cells, Cultured
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Ephrin-A1 / metabolism*
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Growth Cones / physiology
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Monomeric GTP-Binding Proteins / metabolism*
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Neurons / physiology
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Neuropeptides / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Ras Homolog Enriched in Brain Protein
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Rats
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Receptors, Eph Family / metabolism*
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Retina / physiology
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Retinal Ganglion Cells / physiology
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Signal Transduction
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TOR Serine-Threonine Kinases
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Visual Pathways / physiology
Substances
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Brain-Derived Neurotrophic Factor
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Ephrin-A1
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Intracellular Signaling Peptides and Proteins
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Neuropeptides
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Ras Homolog Enriched in Brain Protein
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Rheb protein, mouse
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Tsc2 protein, mouse
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Tsc2 protein, rat
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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mTOR protein, mouse
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Receptors, Eph Family
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Monomeric GTP-Binding Proteins