Tuberous sclerosis complex a paradigm for studying adult neurogenesis and brain tumors

Philippe Taupin, PhD

Abstract


Tuberous sclerosis complex (TSC) is a relatively rare genetic disease characterized by the formation of benign tumors or hamartomas in multiple organs. The tumors are noninvasive and rarely transform to metastatic lesions. TSC is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes. Neurologically, individuals with TSC have severe complications, including refractory seizures, autism, mental retardation, learning difficulties, and changes in behavior. Tubers in the cerebral cortex, subependymal nodules (SENs) along the lateral walls of the lateral ventricles, and subependymal giant cell (GC) astrocytomas are characteristic brain lesions in patients with TSC. Astrocytic-like cells immunopositive for both glial and neuronal markers, dysplastic neurons (DNs), and GCs immunopositive for nestin and vimentin, as well as for proliferation markers such as proliferating nuclear cell antigen (PCNA) and Ki-67, are histological hallmarks of the disease. DNs and GCs retain their ability to re-enter the cell cycle and are immunopositive for markers of neural progenitor and stem cells. Neurogenesis occurs in the adult brain of mammals, particularly in the hippocampus and subventricular zone (SVZ). In the SVZ, newly generated neuronal cells migrate along the ventricle and a SVZ origin for brain tumors in the adult brain have been reported. These brain tumors express markers of neural progenitor and stem cells. The study of analogies and differences between SENs in TSC, neurogenesis in the SVZ, and tumors in the adult brain would reveal clues on the development and origin of SENs and brain tumors.

Keywords: Epilepsy, Cancer, Drug, Disease, Neural stem cells, Rapamycin, Therapy, Tumor

DOI:10.5055/jndr.2013.0012


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Orlova KA, Crino PB: The tuberous sclerosis complex. Ann N Y Acad Sci. 2010; 1184: 87-105.

Gomez MR: Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. Ann N Y Acad Sci. 1991; 615: 1-7.

Cheadle JP, Reeve MP, Sampson JR, et al.: Molecular genetic advances in tuberous sclerosis. Hum Genet. 2000; 107: 97-114.

Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al.: Neurogenesis in the adult human hippocampus. Nat Med. 1998; 4: 1313-1317.

Curtis MA, Kam M, Nannmark U, et al.: Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007; 315: 1243-1249.

Cameron HA, Woolley CS, McEwen BS, et al.: Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience. 1993; 56: 337-344.

Lois C, Alvarez-Buylla A: Long-distance neuronal migration in the adult mammalian brain. Science. 1994; 264: 1145-1148.

Goh S, Butler W, Thiele EA, et al.: Subependymal giant cell tumors in tuberous sclerosis complex. Neurology. 2004; 63: 1457-1461.

Shepherd CW, Gomez MR, Lie JT, et al.: Causes of death in patients with tuberous sclerosis. Mayo Clin Proc. 1991; 66: 792-796.

Curatolo P, Cusmai R, Cortesi F, et al.: Neuropsychiatric aspects of tuberous sclerosis. Ann N Y Acad Sci. 1991; 615: 8-16.

Rakowski SK, Winterkorn EB, Paul E, et al.: Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006; 70: 1777-1782.

Sparagana S, Roach ES: Tuberous sclerosis complex. Curr Opin Neurol. 2000; 13: 115-119.

Crino PB, Nathanson KL, Henske EP: The tuberous sclerosis complex. N Engl J Med. 2006; 355: 1345-1356.

Gillberg IC, Gillberg C, Ahlsen G: Autistic behaviour and attention deficits in tuberous sclerosis: A population-based study. Dev Med Child Neurol. 1994; 36: 50-56.

Smalley SL: Autism and tuberous sclerosis. J Autism Dev Disord. 1998; 28: 407-414.

Joinson C, O’Callaghan FJ, Osborne JP, et al.: Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med. 2003; 33: 335-344.

Prather P, de Vries PJ: Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol. 2004; 19: 666-674.

Thiele EA: Managing epilepsy in tuberous sclerosis complex. J Child Neurol. 2004; 19: 680-686.

Holmes GL, Stafstrom CE: Tuberous sclerosis complex and epilepsy: Recent developments and future challenges. Epilepsia. 2007; 48: 617-630.

Lee A, Maldonado M, Baybis M, et al.: Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol. 2003; 53: 668-673.

Lendahl U, Zimmerman LB, McKay RD: CNS stem cells express a new class of intermediate filament protein. Cell. 1990; 60: 585-595.

Dahlstrand J, Lardelli M, Lendahl U: Nestin mRNA expression correlates with the central nervous system progenitor cell state in many, but not all, regions of developing central nervous system. Brain Res Dev Brain Res. 1995; 84: 109-129.

Kurki P, Vanderlaan M, Dolbeare F, et al.: Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res. 1986; 166: 209-219.

Hall PA, McKee PH, Menage HD, et al.: High levels of p53 protein in UV-irradiated normal human skin. Oncogene. 1993; 8: 203-207.

Takahashi T, Caviness VS Jr: PCNA-binding to DNA at the G1/S transition in proliferating cells of the developing cerebral wall. J Neurocytol. 1993; 22: 1096-1102.

Miller MW, Nowakowski RS: Use of bromodeoxyuridineimmunohistochemistry to examine the proliferation, migration and time of origin of cells in the central nervous system. Brain Res. 1998; 457: 44-52.

Taupin P: BrdU immunohistochemistry for studying adult neurogenesis: Paradigms, pitfalls, limitations, and validation. Brain Res Rev. 2007; 53: 198-214.

Taupin P: Protocols for studying adult neurogenesis: Insights and recent developments. Regen Med. 2007; 2: 51-62.

Shepherd CW, Houser OW, Gomez MR: MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. Am J Neuroradiol. 1995; 16: 149-155.

Crino PB, Trojanowski JQ, Dichter MA, et al.: Embryonic neuronal markers in tuberous sclerosis: Single-cell molecular pathology. Proc Natl Acad Sci USA. 1996; 93: 14152-14157.

Mizuguchi M, Yamanouchi H, Becker LE, et al.: Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia. Acta Neuropathol. 2002; 104: 418-424.

Baybis M, Yu J, Lee A, et al.: mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol. 2004; 56: 478-487.

Boer K, Troost D, Timmermans W, et al.: Cellular localization of metabotropic glutamate receptors in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Neuroscience. 2008; 156: 203-215.

Ure J, Baudry M, Perassolo M: Metabotropic glutamate receptors and epilepsy. J Neurol Sci. 2006; 247: 1-9.

van Slegtenhorst M, de Hoogt R, Hermans C, et al.: Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997; 277: 805-808.

Jones AC, Shyamsundar MM, Thomas MW, et al.: Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet. 1999; 64: 1305-1315.

Sancak O, Nellist M, Goedbloed M, et al.: 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. 2005; 13: 731-741.

York B, Lou D, Panettieri RA Jr, et al.: Cross-talk between tuberin, calmodulin, and estrogen signalling pathways. FASEB J. 2005; 19: 1202-1204.

Yates JR: Tuberous sclerosis. Eur J Hum Genet. 2006; 14: 1065-1073.

Choi YJ, Di Nardo A, Kramvis I, et al.: Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008; 22: 2485-2495.

Huang J, Manning BD: The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. Biochem J. 2008; 412: 179-190.

Chong-Kopera H, Inoki K, Li Y, et al.: TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. J Biol Chem. 2006; 281: 8313-8316.

van Slegtenhorst M, Nellist M, Nagelkerken B, et al.: Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. 1998; 7: 1053-1057.

Inoki K, Li Y, Xu T, et al.: Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003; 17: 1829-1834.

Saucedo LJ, Gao X, Chiarelli DA, et al.: Rheb promotes cell growth as a component of the insulin/TOR signaling network. Nat Cell Biol. 2003; 5: 566-571.

Aspuria PJ, Tamanoi F: The Rheb family of GTP-binding proteins. Cell Signal. 2004; 169: 1105-1112.

The European Chromosome 16 Tuberous Sclerosis Consortium: Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993; 75: 1305-1315.

Napolioni V, Curatolo P: Genetics and molecular biology of tuberous sclerosis complex. Curr Genomics. 2008; 9: 475-487.

Dabora SL, Jozwiak S, Franz DN, et al.: Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet. 2001; 68: 64-80.

Sarbassov DD, Ali SM, Sabatini DM: Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005; 17: 596-603.

Loewith R, Jacinto E, Wullschleger S, et al.: Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002; 10: 457-468.

Sancak Y, Thoreen CC, Peterson TR, et al.: PRAS40 is an insulinregulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007; 25: 903-915.

Jozwiak J, Jozwiak S, Oldak M: Molecular activity of sirolimus and its possible applications in tuberous sclerosis treatment. Med Res Rev. 2006; 26: 160-180.

Bierer BE, Mattila PS, Standaert RF, et al.: Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci USA. 1990; 87: 9231-9235.

Manning BD, Tee AR, Loqsdon MN, et al.: Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002; 10: 151-162.

Tsang CK, Qi H, Liu LF, et al.: Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Disc Today. 2007; 12: 112-124.

Bolster DR, Crozier SJ, Kimball SR, et al.: AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem. 2002; 277: 23977-23980.

Kimura N, Tokunaga C, Dalal S, et al.: A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway. Genes Cell. 2003; 8: 65-79.

Gao X, Zhang Y, Arrazola P, et al.: Tsc tumour suppressor proteins antagonize amino acid-TOR signalling. Nat Cell Biol. 2002; 4: 699-704.

El-Hashemite N, Zhang H, Henske EP, et al.: Mutation in TSC2 and activation of mammalian target of rapamycin signaling pathway in renal angiomyolipoma. Lancet. 2003; 361: 1348-1349.

Burnett PE, Barrow RK, Cohen NA, et al.: RAFT1 phosphorylation of the translational regulators p79 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA. 1998; 95: 1432-1437.

Fingar DC, Salarma S, Tsou C, et al.: Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/ eIF4E. Genes Dev. 2002; 16: 1472-1487.

Chung J, Kuo CJ, Crabtree GR, et al.: Rapamycin-FKBP specifically blocks grown-dependent activation of and signaling by the 70 kD S6 protein kinases. Cell. 1992; 69: 1227-1236.

Guertin DA, Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 2007; 12: 9-22.

Taupin P: Neurogenesis in the adult central nervous system. C R Biol. 2006; 329: 465-475.

Duan X, Kang E, Liu CY, et al.: Development of neural stem cell in the adult brain. Curr Opin Neurobiol. 2008; 18: 108-115.

Toni N, Teng EM, Bushong EA, et al.: Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007; 10: 727-734.

Taupin P: Characterization and isolation of synapses of newly generated neuronal cells of the adult hippocampus at early stages of neurogenesis. J Neurodegener Regen. 2009; 2: 9-17.

Lois C, Garcia-Verdugo JM, Alvarez-Buylla A: Chain migration of neuronal precursors. Science. 1996; 271: 978-981.

Kornack DR, Rakic P: The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proc Natl Acad Sci USA. 2001; 98: 4752-4757.

Gage FH: Mammalian neural stem cells. Science. 2000; 287: 1433-1438.

Taupin P, Gage FH: Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res. 2002; 69: 745-749.

Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992; 255: 1707-1710.

Taupin P, Ray J, Fischer WH, et al.: FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor. Neuron. 2000; 28: 385-397.

Johansson CB, Momma S, Clarke DL, et al.: Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 1999; 96: 25-34.

Doetsch F, Caille I, Lim DA, et al.: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999; 97: 703-716.

Chiasson BJ, Tropepe V, Morshead CM, et al.: Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci. 1999; 19: 4462-4471.

Laywell ED, Rakic P, Kukekov VG, et al.: Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci USA. 2000; 97: 13883-13888.

Seri B, Garcia-Verdugo JM, McEwen BS, et al.: Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci. 2001; 21: 7153-7160.

Hartfuss E, Galli R, Heins N, et al.: Characterization of CNS precursor subtypes and radial glia. Dev Biol. 2001; 229: 15-30.

Miyata T, Kawaguchi A, Okano H, et al.: Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron. 2001; 31: 727-741.

Noctor SC, Flint AC, Weissman TA, et al.: Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J Neurosci. 2002; 22(8): 3161-3173.

Taupin P: Adult neurogenesis, neural stem cells and Alzheimer’s disease: Developments, limitations, problems and promises. Curr Alzhemier Res. 2009; 6: 461-470.

Taupin P: Neurogenesis, NSCs, pathogenesis and therapies for Alzheimer’s disease. Front Biosci. 2011; 3: 178-190.

Kanemura Y, Mori K, Sakakibara S, et al.: Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity. Differentiation. 2001; 68: 141-152.

Toda M, Iizuka Y, Yu W, et al.: Expression of the neural RNA-binding protein Musashi1 in human gliomas. Glia. 2001; 34: 1-7.

Almqvist PM, Mah R, Lendahl U, et al.: Immunohistochemical detection of nestin in pediatric brain tumors. J Histochem Cytochem. 2002; 50: 147-158.

Uchida K, Mukai M, Okano H, et al.: Possible oncogenicity of subventricular zone neural stem cells: Case report. Neurosurgery. 2004; 55: 977-987.

Kwiatkowski DJ, Zhang H, Bandura JL, et al.: A mouse model of TSC1 reveals sexdependent lethality from liver hemangiomas, and upregulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet. 2002; 11: 525-534.

Kobayashi T, Mitani H, Takahashi R, et al.: Transgenic rescue from embryonic lethality and renal carcinogenesis in the Eker rat model by introduction of a wild-type Tsc2 gene. Proc Natl Acad Sci USA. 1997; 94: 3990-3993.

Rennebeck G, Kleymenova EV, Anderson R, et al.: Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci USA. 1998; 95: 15629- 15634.

Kobayashi T, Minowa O, Sugitani Y, et al.: A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc Natl Acad Sci USA. 2001; 98: 8762-8767.

Kwiatkowski DJ: Tuberous sclerosis: From tubers to mTOR. Ann Hum Genet. 2003; 67: 87-96.

Guertin DA, Stevens DM, Thoreen CC, et al.: 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. 2006; 11: 859-871.

Meikle L, Talos DM, Onda H, 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: 5546-5558.

Lee L, Sudentas P, Donohue B, et al.: Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer. 2005; 42: 213-227.

Franz DN, Leonard J, Tudor C, et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006; 59: 490-498.

Bissler JJ, McCormack FX, Young LR, et al.: Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008; 358: 140-151.

Kenerson H, Dundon TA, Yeung RS: Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res. 2005; 57: 67-75.

Motzer RJ, Escudier B, Oudard S, et al.: Phase 3 trial of everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer. 2010; 116: 4256-4265.

Adriaensen ME, Schaefer-Prokop CM, Stijnen T, et al.: Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol. 2009; 16: 691-696.

Yao JC, Shah MH, Ito T, et al.: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 514-523.

Wong M: Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia. 2010; 51: 27-36.

Inoki K, Guan KL: Tuberous sclerosis complex, implication from a rare genetic disease to common cancer treatment. Hum Mol Genet. 2009; 18: R94-R100.

Taupin P: Neurogenic drugs and compounds to treat CNS disorders. Cent Nerv Syst Agents Med Chem. 2011; 11: 35-37.

Taupin P: Adult neurogenesis and neural stem cells as a model for the discovery and development of novel drugs. Expert Opin Drug Discov. 2010; 5: 921-925.

Taupin P: Neurogenic drugs and compounds. Recent Pat CNS Drug Discov. 2010; 5: 253-257.




DOI: https://doi.org/10.5055/jndr.2013.0012

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