title: Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTOR in vivo.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, 85 Xiangya Street, Changsha 410008, China, Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, 85 Xiangya Street, Changsha 410008, China, Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Longbo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, 85 Xiangya Street, Changsha 410008, China, Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Tiffany V
authors.initials: TV
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Miyares
authors.affiliation: Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Hsieh
authors.affiliation: Department of Neurosurgery and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA angelique.bordey@yale.edu.
authors.forename: Angélique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes; D039642:Eukaryotic Initiation Factors; D005260:Female; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3