Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTORin vivo
| Autor: | John H. Wen, Angélique Bordey, Tiffany V. Lin, Longbo Zhang, Xuan Gong, Lawrence S. Hsieh, Laura Miyares, Tianxiang Huang |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Regulator Cell Cycle Proteins P70-S6 Kinase 1 Cell Growth Processes mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Ribosomal Protein S6 Kinases 90-kDa Glycogen Synthase Kinase 3 Mice Eukaryotic initiation factor Genetics medicine Animals Eukaryotic Initiation Factors Axon Molecular Biology Genetics (clinical) PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Glycogen Synthase Kinase 3 beta TOR Serine-Threonine Kinases Translation (biology) Articles General Medicine Phosphoproteins Axons Cell biology Corticogenesis medicine.anatomical_structure Gene Expression Regulation nervous system Multiprotein Complexes Female biological phenomena cell phenomena and immunity Carrier Proteins Signal Transduction |
| Zdroj: | Human Molecular Genetics. 24:5746-5758 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddv295 |
| Popis: | Abnormal axonal connectivity and hyperactive mTOR complex 1 (mTORC1) are shared features of several neurological disorders. Hyperactive mTORC1 alters axon length and polarity of hippocampal neurons in vitro, but the impact of hyperactive mTORC1 on axon growth in vivo and the mechanisms underlying those effects remain unclear. Using in utero electroporation during corticogenesis, we show that increasing mTORC1 activity accelerates axon growth without multiple axon formation. This was prevented by counteracting mTORC1 signaling through p70S6Ks (S6K1/2) or eukaryotic initiation factor 4E-binding protein (4E-BP1/2), which both regulate translation. In addition to regulating translational targets, S6K1 indirectly signals through GSK3β, a regulator of axogenesis. Although blocking GSK3β activity did not alter axon growth under physiological conditions in vivo, blocking it using a dominant-negative mutant or lithium chloride prevented mTORC1-induced accelerated axon growth. These data reveal the contribution of translational and non-translational downstream effectors such as GSK3β to abnormal axon growth in neurodevelopmental mTORopathies and open new therapeutic options for restoring long-range connectivity. |
| Databáze: | OpenAIRE |
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