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The role of TSC1 and TSC2 proteins in neuronal axons

Molecular Psychiatry (2024)Cite this article

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Abstract

Tuberous Sclerosis Complex 1 and 2 proteins, TSC1 and TSC2 respectively, participate in a multiprotein complex with a crucial role for the proper development and function of the nervous system. This complex primarily acts as an inhibitor of the mechanistic target of rapamycin (mTOR) kinase, and mutations in either TSC1 or TSC2 cause a neurodevelopmental disorder called Tuberous Sclerosis Complex (TSC). Neurological manifestations of TSC include brain lesions, epilepsy, autism, and intellectual disability. On the cellular level, the TSC/mTOR signaling axis regulates multiple anabolic and catabolic processes, but it is not clear how these processes contribute to specific neurologic phenotypes. Hence, several studies have aimed to elucidate the role of this signaling pathway in neurons. Of particular interest are axons, as axonal defects are associated with severe neurocognitive impairments. Here, we review findings regarding the role of the TSC1/2 protein complex in axons. Specifically, we will discuss how TSC1/2 canonical and non-canonical functions contribute to the formation and integrity of axonal structure and function.

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Fig. 1: Simplified schematic of the TSC/mTOR axis.
Fig. 2: TSC-mTOR – dependent local protein synthesis in axons.
Fig. 3: The role of Tsc1/2 in axon specification.
Fig. 4: The TSC-mTOR axis regulates myelination during axon development through regionally specific mechanisms and loss of Tsc1/2 function results in hypomyelination.
Fig. 5: The TSC-mTOR axis regulates axon remyelination following injury in a spatiotemporal manner.

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References

  1. Ramón y Cajal S. Histologie du système nerveux de l'homme & des vertébrés. Ed. française rev. & mise à jour par l'auteur, tr. de l'espagnol par L. Azoulay. edn, Vol. v. 1 Maloine; 1909.

  2. Goaillard JM, Moubarak E, Tapia M, Tell F. Diversity of Axonal and Dendritic Contributions to Neuronal Output. Front Cell Neurosci. 2019;13:570.

    Article  PubMed  Google Scholar 

  3. Tahirovic S, Bradke F. Neuronal polarity. Cold Spring Harb Perspect Biol. 2009;1:a001644.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cleveland DW. Neuronal growth and death: order and disorder in the axoplasm. Cell. 1996;84:663–6.

    Article  CAS  PubMed  Google Scholar 

  5. Wegiel J, Kaczmarski W, Flory M, Martinez-Cerdeno V, Wisniewski T, Nowicki K, et al. Deficit of corpus callosum axons, reduced axon diameter and decreased area are markers of abnormal development of interhemispheric connections in autistic subjects. Acta Neuropathol Commun. 2018;6:143.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pijuan I, Balducci E, Soto-Sanchez C, Fernandez E, Barallobre MJ, Arbones ML. Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome. Sci Rep. 2022;12:19912.

    Article  PubMed  PubMed Central  Google Scholar 

  7. DiMario FJ Jr, Sahin M, Ebrahimi-Fakhari D. Tuberous sclerosis complex. Pediatr Clin North Am. 2015;62:633–48.

    Article  PubMed  Google Scholar 

  8. Ruppe V, Dilsiz P, Reiss CS, Carlson C, Devinsky O, Zagzag D, et al. Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and perituberal cortex. Epilepsia. 2014;55:539–50.

    Article  CAS  PubMed  Google Scholar 

  9. de Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, et al. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis. 2018;13:157.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Im K, Ahtam B, Haehn D, Peters JM, Warfield SK, Sahin M, et al. Altered Structural Brain Networks in Tuberous Sclerosis Complex. Cereb Cortex. 2016;26:2046–58.

    Article  PubMed  Google Scholar 

  11. Krishnan ML, Commowick O, Jeste SS, Weisenfeld N, Hans A, Gregas MC, et al. Diffusion features of white matter in tuberous sclerosis with tractography. Pediatr Neurol. 2010;42:101–6.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Makki MI, Chugani DC, Janisse J, Chugani HT. Characteristics of abnormal diffusivity in normal-appearing white matter investigated with diffusion tensor MR imaging in tuberous sclerosis complex. AJNR Am J Neuroradiol. 2007;28:1662–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chandra PS, Salamon N, Huang J, Wu JY, Koh S, Vinters HV, et al. FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report. Epilepsia. 2006;47:1543–9.

    Article  PubMed  Google Scholar 

  14. Peters JM, Sahin M, Vogel-Farley VK, Jeste SS, Nelson CA 3rd, Gregas MC, et al. Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex. Acad Radio. 2012;19:17–25.

    Article  Google Scholar 

  15. Lewis WW, Sahin M, Scherrer B, Peters JM, Suarez RO, Vogel-Farley VK, et al. Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders. Cereb Cortex. 2013;23:1526–32.

    Article  PubMed  Google Scholar 

  16. Peters JM, Struyven RR, Prohl AK, Vasung L, Stajduhar A, Taquet M, et al. White matter mean diffusivity correlates with myelination in tuberous sclerosis complex. Ann Clin Transl Neurol. 2019;6:1178–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Prohl AK, Scherrer B, Tomas-Fernandez X, Davis PE, Filip-Dhima R, Prabhu SP, et al. Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder. J Neurodev Disord. 2019;11:36.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Marcotte L, Crino PB. The neurobiology of the tuberous sclerosis complex. Neuromolecular Med. 2006;8:531–46.

    Article  CAS  PubMed  Google Scholar 

  19. Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J. Molecular neurobiology of mTOR. Neuroscience. 2017;341:112–53.

    Article  CAS  PubMed  Google Scholar 

  20. Han JM, Sahin M. TSC1/TSC2 signaling in the CNS. FEBS Lett. 2011;585:973–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Feliciano DM. The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC). Front Neuroanat. 2020;14:39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci. 2007;27:5546–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Uhlmann EJ, Wong M, Baldwin RL, Bajenaru ML, Onda H, Kwiatkowski DJ, et al. Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol. 2002;52:285–96.

    Article  CAS  PubMed  Google Scholar 

  24. Yeung RS, Katsetos CD, Klein-Szanto A. Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am J Pathol. 1997;151:1477–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Niida Y, Stemmer-Rachamimov AO, Logrip M, Tapon D, Perez R, Kwiatkowski DJ, et al. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am J Hum Genet. 2001;69:493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tucker T, Friedman JM. Pathogenesis of hereditary tumors: beyond the “two-hit” hypothesis. Clin Genet. 2002;62:345–57.

    Article  CAS  PubMed  Google Scholar 

  27. Onda H, Crino PB, Zhang H, Murphey RD, Rastelli L, Gould Rothberg BE, et al. Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol Cell Neurosci. 2002;21:561–74.

    Article  CAS  PubMed  Google Scholar 

  28. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–8.

    Article  PubMed  Google Scholar 

  29. European Chromosome 16 Tuberous Sclerosis, C. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–15.

    Article  Google Scholar 

  30. Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412:179–90.

    Article  CAS  PubMed  Google Scholar 

  31. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell. 2012;47:535–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang H, Yu Z, Chen X, Li J, Li N, Cheng J, et al. Structural insights into TSC complex assembly and GAP activity on Rheb. Nat Commun. 2021;12:339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Capo-Chichi JM, Tcherkezian J, Hamdan FF, Decarie JC, Dobrzeniecka S, Patry L, et al. Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. J Med Genet. 2013;50:740–4.

    Article  CAS  PubMed  Google Scholar 

  34. Alfaiz AA, Micale L, Mandriani B, Augello B, Pellico MT, Chrast J, et al. TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. Hum Mutat. 2014;35:447–51.

    Article  PubMed  Google Scholar 

  35. Schrotter S, Yuskaitis CJ, MacArthur MR, Mitchell SJ, Hosios AM, Osipovich M, et al. The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth. Cell Rep. 2022;39:110824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci. 2014;7:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rosner M, Hanneder M, Siegel N, Valli A, Hengstschlager M. The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutat Res. 2008;658:234–46.

    Article  CAS  PubMed  Google Scholar 

  38. Wu Y, Zhou BP. Kinases meet at TSC. Cell Res. 2007;17:971–3.

    Article  CAS  PubMed  Google Scholar 

  39. Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland AM, Halley DJ, van der Sluijs P. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J Biol Chem. 1999;274:35647–52.

    Article  CAS  PubMed  Google Scholar 

  40. Plank TL, Yeung RS, Henske EP. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res. 1998;58:4766–70.

    CAS  PubMed  Google Scholar 

  41. Zhang J, Kim J, Alexander A, Cai S, Tripathi DN, Dere R, et al. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat Cell Biol. 2013;15:1186–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wienecke R, Maize JC Jr, Shoarinejad F, Vass WC, Reed J, Bonifacino JS, et al. Co-localization of the TSC2 product tuberin with its target Rap1 in the Golgi apparatus. Oncogene. 1996;13:913–23.

    CAS  PubMed  Google Scholar 

  43. Haddad LA, Smith N, Bowser M, Niida Y, Murthy V, Gonzalez-Agosti C, et al. The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton. J Biol Chem. 2002;277:44180–6.

    Article  CAS  PubMed  Google Scholar 

  44. Choi YJ, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski DJ, Sahin M, et al. Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008;22:2485–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Poulopoulos A, Murphy AJ, Ozkan A, Davis P, Hatch J, Kirchner R, et al. Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex. Nature. 2019;565:356–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Norambuena A, Sun X, Wallrabe H, Cao R, Sun N, Pardo E, et al. SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-beta oligomers. Neurobiol Dis. 2022;169:105737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb. Curr Biol. 2022;32:733–4.

    Article  CAS  PubMed  Google Scholar 

  48. Hansmann P, Bruckner A, Kiontke S, Berkenfeld B, Seebohm G, Brouillard P, et al. Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations. Structure. 2020;28:933–42.e934.

    Article  CAS  PubMed  Google Scholar 

  49. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chong-Kopera H, Inoki K, Li Y, Zhu T, Garcia-Gonzalo FR, Rosa JL, et al. TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J Biol Chem. 2006;281:8313–6.

    Article  CAS  PubMed  Google Scholar 

  51. Nakashima A, Yoshino K, Miyamoto T, Eguchi S, Oshiro N, Kikkawa U, et al. Identification of TBC7 having TBC domain as a novel binding protein to TSC1-TSC2 complex. Biochem Biophys Res Commun. 2007;361:218–23.

    Article  CAS  PubMed  Google Scholar 

  52. Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol. 2008;28:4104–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans. 2009;37:217–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Godel M, Fischer S, et al. A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal. 2012;5:ra25.

    PubMed  Google Scholar 

  55. Karalis V, Caval-Holme F, Bateup HS. Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex. Nat Commun. 2022;13:4665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Weston MC, Chen H, Swann JW. Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures. Front Mol Neurosci. 2014;7:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang J, Wu S, Wu CL, Manning BD. Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res. 2009;69:6107–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McCabe MP, Cullen ER, Barrows CM, Shore AN, Tooke KI, Laprade KA, et al. Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission. Elife. 2020;9:e51440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen CJ, Sgritta M, Mays J, Zhou H, Lucero R, Park J, et al. Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency. Nat Med. 2019;25:1684–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Angliker N, Ruegg MA. In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons. Bioarchitecture. 2013;3:113–8.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14:1296–302.

    Article  CAS  PubMed  Google Scholar 

  62. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–8.

    Article  CAS  PubMed  Google Scholar 

  63. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168:960–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Karalis V, Bateup HS. Current Approaches and Future Directions for the Treatment of mTORopathies. Dev Neurosci. 2021;43:143–58.

    Article  CAS  PubMed  Google Scholar 

  65. Crino PB. mTORopathies: A Road Well-Traveled. Epilepsy Curr. 2020;20:64S–66S.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014;84:275–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jung H, Yoon BC, Holt CE. Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair. Nat Rev Neurosci. 2012;13:308–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Korsak LI, Mitchell ME, Shepard KA, Akins MR. Regulation of neuronal gene expression by local axonal translation. Curr Genet Med Rep. 2016;4:16–25.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Twiss JL, Kalinski AL, Sachdeva R, Houle JD. Intra-axonal protein synthesis - a new target for neural repair? Neural Regen Res. 2016;11:1365–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Spaulding EL, Burgess RW. Accumulating Evidence for Axonal Translation in Neuronal Homeostasis. Front Neurosci. 2017;11:312.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kaplan BB, Gioio AE, Hillefors M, Aschrafi A. Axonal protein synthesis and the regulation of local mitochondrial function. Results Probl Cell Differ. 2009;48:225–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Holt CE, Martin KC, Schuman EM. Local translation in neurons: visualization and function. Nat Struct Mol Biol. 2019;26:557–66.

    Article  CAS  PubMed  Google Scholar 

  73. Altas B, Romanowski AJ, Bunce GW, Poulopoulos A. Neuronal mTOR Outposts: Implications for Translation, Signaling, and Plasticity. Front Cell Neurosci. 2022;16:853634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jia JJ, Lahr RM, Solgaard MT, Moraes BJ, Pointet R, Yang AD, et al. mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1. Nucleic Acids Res. 2021;49:3461–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21:183–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tang SJ, Reis G, Kang H, Gingras AC, Sonenberg N, Schuman EM. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci USA. 2002;99:467–72.

    Article  CAS  PubMed  Google Scholar 

  77. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001;15:807–26.

    Article  CAS  PubMed  Google Scholar 

  78. Tyagi R, Shahani N, Gorgen L, Ferretti M, Pryor W, Chen PY, et al. Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2alpha Signaling Cascade. Cell Rep. 2015;10:684–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nie D, Chen Z, Ebrahimi-Fakhari D, Di Nardo A, Julich K, Robson VK, et al. The Stress-Induced Atf3-Gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex. J Neurosci. 2015;35:10762–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sare RM, Huang T, Burlin T, Loutaev I, Smith CB. Decreased rates of cerebral protein synthesis measured in vivo in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin. J Neurochem. 2018;145:417–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Auerbach BD, Osterweil EK, Bear MF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature. 2011;480:63–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chiaradia E, Miller I, Renzone G, Tognoloni A, Polchi A, De Marco F, et al. Proteomic analysis of murine Tsc1-deficient neural stem progenitor cells. J Proteom. 2023;283-284:104928.

    Article  CAS  Google Scholar 

  83. Sundberg M, Tochitsky I, Buchholz DE, Winden K, Kujala V, Kapur K, et al. Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin. Mol Psychiatry. 2018;23:2167–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Terenzio M, Koley S, Samra N, Rishal I, Zhao Q, Sahoo PK, et al. Locally translated mTOR controls axonal local translation in nerve injury. Science. 2018;359:1416–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen X, Shi Z, Yang F, Zhou T, Xie S. Deciphering cilia and ciliopathies using proteomic approaches. FEBS J. 2022;290:2590–603.

    Article  PubMed  Google Scholar 

  86. Barnes AP, Polleux F. Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci. 2009;32:347–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. de la Torre-Ubieta L, Bonni A. Transcriptional regulation of neuronal polarity and morphogenesis in the mammalian brain. Neuron. 2011;72:22–40.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Takano T, Funahashi Y, Kaibuchi K. Neuronal Polarity: Positive and Negative Feedback Signals. Front Cell Dev Biol. 2019;7:69.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Arimura N, Kaibuchi K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci. 2007;8:194–205.

    Article  CAS  PubMed  Google Scholar 

  90. Poulain FE, Sobel A. The microtubule network and neuronal morphogenesis: Dynamic and coordinated orchestration through multiple players. Mol Cell Neurosci. 2010;43:15–32.

    Article  CAS  PubMed  Google Scholar 

  91. Mejia LA, Litterman N, Ikeuchi Y, de la Torre-Ubieta L, Bennett EJ, Zhang C, et al. A novel Hap1-Tsc1 interaction regulates neuronal mTORC1 signaling and morphogenesis in the brain. J Neurosci. 2013;33:18015–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Umegaki Y, Brotons AM, Nakanishi Y, Luo Z, Zhang H, Bonni A, et al. Palladin Is a Neuron-Specific Translational Target of mTOR Signaling That Regulates Axon Morphogenesis. J Neurosci. 2018;38:4985–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li YH, Werner H, Puschel AW. Rheb and mTOR regulate neuronal polarity through Rap1B. J Biol Chem. 2008;283:33784–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ohsawa M, Kobayashi T, Okura H, Igarashi T, Mizuguchi M, Hino O. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLoS One. 2013;8:e54503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dotti CG, Sullivan CA, Banker GA. The establishment of polarity by hippocampal neurons in culture. J Neurosci. 1988;8:1454–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fukata Y, Kimura T, Kaibuchi K. Axon specification in hippocampal neurons. Neurosci Res. 2002;43:305–15.

    Article  CAS  PubMed  Google Scholar 

  97. Kosillo P, Ahmed KM, Aisenberg EE, Karalis V, Roberts BM, Cragg SJ, et al. Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2. Elife. 2022;11:e75398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gong X, Zhang L, Huang T, Lin TV, Miyares L, Wen J, et al. Activating the translational repressor 4E-BP or reducing S6K-GSK3beta activity prevents accelerated axon growth induced by hyperactive mTOR in vivo. Hum Mol Genet. 2015;24:5746–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Schwamborn JC, Puschel AW. The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci. 2004;7:923–9.

    Article  CAS  PubMed  Google Scholar 

  100. Morita T, Sobue K. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J Biol Chem. 2009;284:27734–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lowery LA, Van Vactor D. The trip of the tip: understanding the growth cone machinery. Nat Rev Mol Cell Biol. 2009;10:332–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Knox S, Ge H, Dimitroff BD, Ren Y, Howe KA, Arsham AM, et al. Mechanisms of TSC-mediated control of synapse assembly and axon guidance. PLoS One. 2007;2:e375.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Canal I, Acebes A, Ferrus A. Single neuron mosaics of the drosophila gigas mutant project beyond normal targets and modify behavior. J Neurosci. 1998;18:999–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Flanagan JG. Neural map specification by gradients. Curr Opin Neurobiol. 2006;16:59–66.

    Article  CAS  PubMed  Google Scholar 

  105. Scicolone G, Ortalli AL, Carri NG. Key roles of Ephs and ephrins in retinotectal topographic map formation. Brain Res Bull. 2009;79:227–47.

    Article  CAS  PubMed  Google Scholar 

  106. Nie D, Di Nardo A, Han JM, Baharanyi H, Kramvis I, Huynh T, et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci. 2010;13:163–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Catlett TS, Onesto MM, McCann AJ, Rempel SK, Glass J, Franz DN, et al. RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex. Nat Commun. 2021;12:2589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, et al. Local translation of RhoA regulates growth cone collapse. Nature. 2005;436:1020–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, et al. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol. 2000;2:281–7.

    Article  CAS  PubMed  Google Scholar 

  110. Mahar M, Cavalli V. Intrinsic mechanisms of neuronal axon regeneration. Nat Rev Neurosci. 2018;19:323–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Huebner EA, Strittmatter SM. Axon regeneration in the peripheral and central nervous systems. Results Probl Cell Differ. 2009;48:339–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322:963–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010;13:1075–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Karbowniczek M, Cash T, Cheung M, Robertson GP, Astrinidis A, Henske EP. Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. J Biol Chem. 2004;279:29930–7.

    Article  CAS  PubMed  Google Scholar 

  115. Huang T, Karsy M, Zhuge J, Zhong M, Liu D. B-Raf and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. O’Donovan KJ, Ma K, Guo H, Wang C, Sun F, Han SB, et al. B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS. J Exp Med. 2014;211:801–14.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Suminaite D, Lyons DA, Livesey MR. Myelinated axon physiology and regulation of neural circuit function. Glia. 2019;67:2050–62.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485:517–21.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012;487:443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fields RD. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci. 2015;16:756–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Almeida RG, Lyons DA. On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function. J Neurosci. 2017;37:10023–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Arulrajah S, Ertan G, Jordan L, Tekes A, Khaykin E, Izbudak I, et al. Magnetic resonance imaging and diffusion-weighted imaging of normal-appearing white matter in children and young adults with tuberous sclerosis complex. Neuroradiology. 2009;51:781–6.

    Article  PubMed  Google Scholar 

  123. Muhlebner A, van Scheppingen J, de Neef A, Bongaarts A, Zimmer TS, Mills JD, et al. Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers. J Neuropathol Exp Neurol. 2020;79:1054–64.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Figlia G, Gerber D, Suter U. Myelination and mTOR. Glia. 2018;66:693–707.

    Article  PubMed  Google Scholar 

  125. Emery B, Lu QR. Transcriptional and Epigenetic Regulation of Oligodendrocyte Development and Myelination in the Central Nervous System. Cold Spring Harb Perspect Biol. 2015;7:a020461.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Elbaz B, Popko B. Molecular Control of Oligodendrocyte Development. Trends Neurosci. 2019;42:263–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Pfeiffer SE, Warrington AE, Bansal R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 1993;3:191–7.

    Article  CAS  PubMed  Google Scholar 

  128. Thomason EJ, Escalante M, Osterhout DJ, Fuss B. The oligodendrocyte growth cone and its actin cytoskeleton: A fundamental element for progenitor cell migration and CNS myelination. Glia. 2020;68:1329–46.

    Article  PubMed  Google Scholar 

  129. Jiang M, Liu L, He X, Wang H, Lin W, Wang H, et al. Regulation of PERK-eIF2alpha signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes. Nat Commun. 2016;7:12185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Carson RP, Kelm ND, West KL, Does MD, Fu C, Weaver G, et al. Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors. Ann Clin Transl Neurol. 2015;2:1041–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lebrun-Julien F, Bachmann L, Norrmen C, Trotzmuller M, Kofeler H, Ruegg MA, et al. Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. J Neurosci. 2014;34:8432–48.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Shi Q, Saifetiarova J, Taylor AM, Bhat MA. mTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization. Front Cell Neurosci. 2018;12:201.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Tognatta R, Sun W, Goebbels S, Nave KA, Nishiyama A, Schoch S, et al. Transient Cnp expression by early progenitors causes Cre-Lox-based reporter lines to map profoundly different fates. Glia. 2017;65:342–59.

    Article  PubMed  Google Scholar 

  134. Rawson RB. The SREBP pathway–insights from Insigs and insects. Nat Rev Mol Cell Biol. 2003;4:631–40.

    Article  CAS  PubMed  Google Scholar 

  135. Bercury KK, Dai J, Sachs HH, Ahrendsen JT, Wood TL, Macklin WB. Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination. J Neurosci. 2014;34:4466–80.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Khandker L, Jeffries MA, Chang YJ, Mather ML, Evangelou AV, Bourne JN, et al. Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between brain and spinal cord. Cell Rep. 2022;38:110423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ornelas IM, McLane LE, Saliu A, Evangelou AV, Khandker L, Wood TL. Heterogeneity in oligodendroglia: Is it relevant to mouse models and human disease? J Neurosci Res. 2016;94:1421–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Schule M, Butto T, Dewi S, Schlichtholz L, Strand S, Gerber S, et al. mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex. Int J Mol Sci. 2021;22:6034.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Ercan E, Han JM, Di Nardo A, Winden K, Han MJ, Hoyo L, et al. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. J Exp Med. 2017;214:681–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zou J, Zhou L, Du XX, Ji Y, Xu J, Tian J, et al. Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev Cell. 2011;20:97–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kosillo P, Doig NM, Ahmed KM, Agopyan-Miu A, Wong CD, Conyers L, et al. Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility. Nat Commun. 2019;10:5426.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Castelnovo LF, Bonalume V, Melfi S, Ballabio M, Colleoni D, Magnaghi V. Schwann cell development, maturation and regeneration: a focus on classic and emerging intracellular signaling pathways. Neural Regen Res. 2017;12:1013–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Figlia G, Norrmen C, Pereira JA, Gerber D, Suter U. Dual function of the PI3K-Akt-mTORC1 axis in myelination of the peripheral nervous system. Elife. 2017;6:e29241.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Jiang M, Rao R, Wang J, Wang J, Xu L, Wu LM, et al. The TSC1-mTOR-PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage-specific manner. Glia. 2018;66:1947–59.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Beirowski B, Wong KM, Babetto E, Milbrandt J. mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells. Proc Natl Acad Sci USA. 2017;114:E4261–E4270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:177–89.

    Article  CAS  PubMed  Google Scholar 

  147. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110:163–75.

    Article  CAS  PubMed  Google Scholar 

  148. Tyler WA, Gangoli N, Gokina P, Kim HA, Covey M, Levison SW, et al. Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. J Neurosci. 2009;29:6367–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Musah AS, Brown TL, Jeffries MA, Shang Q, Hashimoto H, Evangelou AV, et al. Mechanistic Target of Rapamycin Regulates the Oligodendrocyte Cytoskeleton during Myelination. J Neurosci. 2020;40:2993–3007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Norrmen C, Figlia G, Lebrun-Julien F, Pereira JA, Trotzmuller M, Kofeler HC, et al. mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells. Cell Rep. 2014;9:646–60.

    Article  CAS  PubMed  Google Scholar 

  151. Sherman DL, Krols M, Wu LM, Grove M, Nave KA, Gangloff YG, et al. Arrest of myelination and reduced axon growth when Schwann cells lack mTOR. J Neurosci. 2012;32:1817–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Dahl KD, Almeida AR, Hathaway HA, Bourne J, Brown TL, Finseth LT, et al. mTORC2 Loss in Oligodendrocyte Progenitor Cells Results in Regional Hypomyelination in the Central Nervous System. J Neurosci. 2023;43:540–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wahl SE, McLane LE, Bercury KK, Macklin WB, Wood TL. Mammalian target of rapamycin promotes oligodendrocyte differentiation, initiation and extent of CNS myelination. J Neurosci. 2014;34:4453–65.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8:224–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lewis CA, Griffiths B, Santos CR, Pende M, Schulze A. Regulation of the SREBP transcription factors by mTORC1. Biochem Soc Trans. 2011;39:495–9.

    Article  CAS  PubMed  Google Scholar 

  156. Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 2011;14:21–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Fedder-Semmes KN, Appel B. The Akt-mTOR Pathway Drives Myelin Sheath Growth by Regulating Cap-Dependent Translation. J Neurosci. 2021;41:8532–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Narayanan SP, Flores AI, Wang F, Macklin WB. Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J Neurosci. 2009;29:6860–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22:159–68.

    Article  CAS  PubMed  Google Scholar 

  160. Gonzalez-Fernandez E, Jeong HK, Fukaya M, Kim H, Khawaja RR, Srivastava IN, et al. PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling. Elife. 2018;7:e32021.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Ludwin SK. Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest. 1978;39:597–612.

    CAS  PubMed  Google Scholar 

  162. Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008;9:839–55.

    Article  CAS  PubMed  Google Scholar 

  163. Baaklini CS, Rawji KS, Duncan GJ, Ho MFS, Plemel JR. Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells. Front Mol Neurosci. 2019;12:225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Orthmann-Murphy J, Call CL, Molina-Castro GC, Hsieh YC, Rasband MN, Calabresi PA, et al. Remyelination alters the pattern of myelin in the cerebral cortex. Elife. 2020;9:e56621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chen ZL, Yu WM, Strickland S. Peripheral regeneration. Annu Rev Neurosci. 2007;30:209–33.

    Article  PubMed  Google Scholar 

  166. Balakrishnan A, Belfiore L, Chu TH, Fleming T, Midha R, Biernaskie J, et al. Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury. Front Mol Neurosci. 2020;13:608442.

    Article  CAS  PubMed  Google Scholar 

  167. McLane LE, Bourne JN, Evangelou AV, Khandker L, Macklin WB, Wood TL. Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells Enhances Axon Remyelination and Increases Myelin Thickness after a Focal Demyelination. J Neurosci. 2017;37:7534–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sachs HH, Bercury KK, Popescu DC, Narayanan SP, Macklin WB. A new model of cuprizone-mediated demyelination/remyelination. ASN Neuro. 2014;6:1759091414551955.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Jeffries MA, McLane LE, Khandker L, Mather ML, Evangelou AV, Kantak D, et al. mTOR Signaling Regulates Metabolic Function in Oligodendrocyte Precursor Cells and Promotes Efficient Brain Remyelination in the Cuprizone Model. J Neurosci. 2021;41:8321–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Norrmen C, Figlia G, Pfistner P, Pereira JA, Bachofner S, Suter U. mTORC1 Is Transiently Reactivated in Injured Nerves to Promote c-Jun Elevation and Schwann Cell Dedifferentiation. J Neurosci. 2018;38:4811–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kothare SV, Singh K, Chalifoux JR, Staley BA, Weiner HL, Menzer K, et al. Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia. 2014;55:1025–9.

    Article  CAS  PubMed  Google Scholar 

  172. Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021;123:50–66.

    Article  PubMed  Google Scholar 

  173. Pallet N, Legendre C. Adverse events associated with mTOR inhibitors. Expert Opin Drug Saf. 2013;12:177–86.

    Article  CAS  PubMed  Google Scholar 

  174. Sager RA, Woodford MR, Mollapour M. The mTOR Independent Function of Tsc1 and FNIPs. Trends Biochem Sci. 2018;43:935–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Neuman NA, Henske EP. Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis. EMBO Mol Med. 2011;3:189–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Lai M, Zou W, Han Z, Zhou L, Qiu Z, Chen J, et al. Tsc1 regulates tight junction independent of mTORC1. Proc Natl Acad Sci USA. 2021;118:e2020891118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Catherine L. Salussolia for critical reading of this manuscript.

Funding

This work was supported by the NIH (R01NS113591 and P50HD105351 to MS, T32NS007473 training grant to VK).

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Authors and Affiliations

  1. Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Vasiliki Karalis, Nicole A. Teaney & Mustafa Sahin

  2. FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, 02115, USA

    Vasiliki Karalis, Delaney Wood, Nicole A. Teaney & Mustafa Sahin

  3. Human Neuron Core, Boston Children’s Hospital, Boston, MA, 02115, USA

    Delaney Wood & Mustafa Sahin

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  1. Vasiliki Karalis
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All authors outlined, drafted, and edited the review text. VK, NAT and DW prepared the figures. All authors read and approved the final manuscript.

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Correspondence to Mustafa Sahin.

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Competing interests

MS reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes.

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Karalis, V., Wood, D., Teaney, N.A. et al. The role of TSC1 and TSC2 proteins in neuronal axons. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02402-7

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