MTOR signaling in neural stem cells: From basic biology to disease

Cellular and Molecular Life Sciences

Volumn 70, Issue 16, 2013, Pages 2887-2898

  Magri, Laura ^a   Galli, Rossella ^a  

^a SAN RAFFAELE HOSPITAL   (Italy)

Author keywords

mTOR; Neural stem cells; Tuberous sclerosis complex

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2;

CELL COMPARTMENTALIZATION; CELL METABOLISM; DISEASE ASSOCIATION; ENZYME ACTIVATION; ENZYME ACTIVITY; HUMAN; MOLECULAR PATHOLOGY; NEGATIVE FEEDBACK; NEURAL STEM CELL; NONHUMAN; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS REGULATION; REVIEW; SIGNAL TRANSDUCTION; TUBEROUS SCLEROSIS;

ANIMALS; HAMARTOMA SYNDROME, MULTIPLE; HUMANS; METABOLIC DISEASES; NEOPLASMS; NEURAL STEM CELLS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

ANIMALIA; MAMMALIA;

EID: 84881162906     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-012-1196-x     Document Type: Review

References (112)

1. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274-293
2. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9-22
3. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21-35
4. Chen C, et al. (2008) TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 205(10):2397-2408
5. Castilho RM, et al. (2009) mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 5(3):279-289
6. Hobbs RM, et al. (2010) Plzf regulates germline progenitor self-renewal by opposing mTORC1. Cell 142(3):468-479
7. Sun P, et al. (2010) TSC1/2 tumour suppressor complex maintains Drosophila germline stem cells by preventing differentiation. Development 137(15):2461-2469
8. Magri L, et al. (2011) Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell 9(5):447-462
9. Carson RP, et al. (2011) Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis 45(1):369-380
10. Hara K, et al. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177-189
11. Sarbassov DD, et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296-1302
12. Guertin DA, et al. (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859-871
13. Loewith R, et al. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10(3):457-468
14. Kim DH, et al. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163-175
15. Sarbassov DD, et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159-168
16. Sabatini DM, et al. (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78(1):35-43
17. Huang J, et al. (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28(12):4104-4115
18. Saucedo LJ, et al. (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5(6):566-571
19. Manning BD, et al. (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10(1):151-162
20. Inoki K, et al. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4(9):648-657
21. Sancak Y, et al. (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25(6):903-915
22. Ma L, et al. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121(2):179-193
23. Jozwiak J, Jozwiak S, Wlodarski P (2008) Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol 9(1):73-79
24. Lee DF, et al. (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130(3):440-455
25. Inoki K, et al. (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126(5):955-968
26. Hara K, et al. (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273(23):14484-14494
27. Kim E, et al. (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10(8):935-945
28. Sancak Y, et al. (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496-1501
29. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577-590
30. Hahn-Windgassen A, et al. (2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280(37):32081-32089
31. Shaw RJ, et al. (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91-99
32. Brugarolas J, et al. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18(23):2893-2904
33. Hara K, et al. (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 272(42):26457-26463
34. Miyata H, Chiang AC, Vinters HV (2004) Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol 56(4):510-519
35. Chan JA, et al. (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 63(12):1236-1242
36. Yu Y, et al. (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332(6035):1322-1326
37. Hsu PP, et al. (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332(6035):1317-1322
38. Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol (CB) 19(22):R1046-R1052
39. Duvel K, et al. (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39(2):171-183
40. Li S, Brown MS, Goldstein JL (2010) Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA 107(8):3441-3446
41. Brugarolas JB, et al. (2003) TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4(2):147-158
42. Ganley IG, et al. (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284(18):12297-12305
43. Hosokawa N, et al. (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20(7):1981-1991
44. Um SH, et al. (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431(7005):200-205
45. Kwiatkowski DJ, et al. (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11(5):525-534
46. Zhang H, et al. (2007) PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117(3):730-738
47. Jacinto E, et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122-1128
48. Dalle Pezze P, et al. (2012) A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal 5(217):ra25
49. Lamming DW, et al. (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335(6076):1638-1643
50. Sarbassov DD, et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098-1101
51. Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416(3):375-385
52. Neuman, NA, Henske EP (2011) Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis. EMBO Mol Med 3(4):189-200
53. Astrinidis A, Senapedis W, Henske EP (2006) Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet 15(2):287-297
54. Bonnet CS, et al. (2009) Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Hum Mol Genet 18(12):2166-2176
55. Zhou X, et al. (2009) Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proc Natl Acad Sci USA 106(22):8923-8928
56. Inoki K, et al. (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17(15):1829-1834
57. Freilinger A, et al. (2006) Tuberin activates the proapoptotic molecule BAD. Oncogene 25(49):6467-6479
58. Di Nardo A, et al. (2009) Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. J Neurosci Off J Soc Neurosci 29(18):5926-5937
59. Thoreen CC, et al. (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023-8032
60. Russell RC, Fang C, Guan KL (2011) An emerging role for TOR signaling in mammalian tissue and stem cell physiology. Development 138(16):3343-3356
61. Yilmaz OH, et al. (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441(7092):475-482
62. Chen C, Liu Y, Zheng P (2009) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2(98):ra75
63. Chen C, Liu Y, Zheng P (2010) Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice. J Clin Investig 120(11):4091-4101
64. Murakami M, et al. (2004) mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 24(15):6710-6718
65. Zhou J, et al. (2009) mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. Proc Natl Acad Sci USA 106(19):7840-7845
66. Easley CAt, et al. (2010) mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram 12(3):263-273
67. Chen T, et al. (2011) Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10(5):908-911
68. He J, et al. (2012) An elaborate regulation of mammalian target of rapamycin activity is required for somatic cell reprogramming induced by defined transcription factors. Stem Cells Dev 21(14):2630-2641
69. Sancak O, et al. (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet 13(6):731-741
70. Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355(13):1345-1356
71. Thiele EA (2004) Managing epilepsy in tuberous sclerosis complex. J Child Neurol 19(9):680-686
72. Crino PB (2011) mTOR: a pathogenic signaling pathway in developmental brain malformations. Trends Mol Med 17(12):734-742
73. Crino PB, Henske EP (1999) New developments in the neurobiology of the tuberous sclerosis complex. Neurology 53(7):1384-1390
74. Kim SK, et al. (2001) Biological behavior and tumorigenesis of subependymal giant cell astrocytomas. J Neurooncol 52(3):217-225
75. Marcotte L, Crino PB (2006) The neurobiology of the tuberous sclerosis complex. Neuromolecular Med 8(4):531-546
76. Henske EP, et al. (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 59(2):400-406
77. Henske EP, et al. (1997) Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol 151(6):1639-1647
78. Crino PB, et al. (2010) Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 74(21):1716-1723
79. Doetsch F (2003) The glial identity of neural stem cells. Nat Neurosci 6(11):1127-1134
80. Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149-184
81. Gotz M, Barde YA (2005) Radial glial cells defined and major intermediates between embryonic stem cells and CNS neurons. Neuron 46(3):369-372
82. Noctor SC, et al. (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7(2):136-144
83. Gage FH (2002) Neurogenesis in the adult brain. J Neurosci 22(3):612-613
84. Doetsch F, et al. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97(6):703-716
85. Young KM, et al. (2007) Subventricular zone stem cells are heterogeneous with respect to their embryonic origins and neurogenic fates in the adult olfactory bulb. J Neurosci 27(31):8286-8296
86. Merkle FT, Mirzadeh Z, Alvarez-Buylla A (2007) Mosaic organization of neural stem cells in the adult brain. Science 317(5836):381-384
87. Seri B, et al. (2004) Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 478(4):359-378
88. Sanai N, et al. (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427(6976):740-744
89. Sanai N, et al. (2011) Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478(7369):382-386
90. Fietz SA, et al. (2010) OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci 13(6):690-699
91. Hansen DV, et al. (2010) Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464(7288):554-561
92. Dehay C, Kennedy H (2007) Cell-cycle control and cortical development. Nat Rev Neurosci 8(6):438-450
93. Holmes GL, Stafstrom CE (2007) Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 48(4):617-630
94. Ridler K, et al. (2004) Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. J Child Neurol 19(9):658-665
95. Lee A, et al. (2003) Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol 53(5):668-673
96. Ess KC, et al. (2005) Developmental origin of subependymal giant cell astrocytoma in tuberous sclerosis complex. Neurology 64(8):1446-1449
97. Zhou J, et al. (2011) Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev 25(15):1595-1600
98. Way SW, et al. (2009) Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum Mol Genet 18(7):1252-1265
99. Uhlmann EJ, et al. (2002) Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol 52(3):285-296
100. Meikle L, et al. (2007) A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 27(21):5546-5558
101. Ehninger D, et al. (2008) Reversal of learning deficits in a Tsc2± mouse model of tuberous sclerosis. Nat Med 14(8):843-848
102. Zeng LH, et al. (2011) Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of Tuberous Sclerosis Complex. Hum Mol Genet 20(3):445-454
103. Fu C, et al. (2011) GABAergic interneuron development and function is modulated by the Tsc1. Gene Cereb Cortex 22(9):2111-2119
104. Feliciano DM, et al. (2011) Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J Clin Invest 121(4):1596-1607
105. Feliciano DM, et al. (2011) Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion. Hum Mol Genet 21(4):799-810
106. Gorski JA, et al. (2002) Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci 22(15):6309-6314
107. Anderl S, et al. (2011) Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum Mol Genet 20(23):4597-4604
108. Goto J, et al. (2011) Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci USA 108(45):E1070-E1079
109. Meikle L, et al. (2008) Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 28(21):5422-5432
110. Zeng LH, et al. (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63(4):444-453
111. Way SW, et al. (2012) The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum Mol Genet 21(14):3226-3236
112. Onda H, et al. (2002) Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol Cell Neurosci 21(4):561-574