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01.08.2004 | Regular Paper

Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis

verfasst von: H. Jürgen Wenzel, Leena S. Patel, Carol A. Robbins, Adriana Emmi, Raymond S. Yeung, Philip A. Schwartzkroin

Erschienen in: Acta Neuropathologica | Ausgabe 2/2004

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Abstract

Tuberous sclerosis (TSC) is an autosomal dominant disorder, caused by mutations of either the TSC1 or TSC2 gene. Characteristic brain pathologies (including cortical tubers and subependymal hamartomas/giant astrocytomas) are thought to cause epilepsy, as well as other neurological dysfunction. The Eker rat, which carries a spontaneous germline mutation of the TSC2 gene (TSC2^+/−), provides a unique animal model in which to study the relationship between TSC cortical pathologies and epilepsy. In the present study, we have analyzed the seizure propensity and histopathological features of a modified Eker rat preparation, in which early postnatal irradiation was employed as a “second hit” stimulus in an attempt to exacerbate cortical malformations and increase seizure propensity. Irradiated Eker rats had a tendency toward lower seizure thresholds (latencies to flurothyl-induced seizures) than seen in non-irradiated Eker rats (significant difference) or irradiated wild-type rats (non-significant difference). The majority of irradiated Eker rats exhibited dysplastic cytomegalic neurons and giant astrocyte-like cells, similar to cytopathologies observed in TSC lesions of patients. The most prominent features in these brains were hamartoma-like lesions involving large eosinophilic cells, similar to giant tuber cells in human TSC. In some cells from these hamartomas, immunocytochemistry revealed features of both neuronal and glial phenotypes, suggesting an undifferentiated or immature cell population. Both normal-appearing and dysmorphic neurons, as well as cells in the hamartomas, exhibited immunopositivity for tuberin, the protein product of the TSC2 gene.

Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ, Fujikawa K, Bjornsson J, Bernstein J, Henske EP (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208–2216PubMed

Arai Y, Ackerley CA, Becker LE (1999) Loss of the TSC2 product tuberin in subependymal giant-cell tumors. Acta Neuropathol 98:233–239CrossRefPubMed

Arai Y, Edwards V, Becker LE (1999) A comparison of cell phenotypes in hemimegalencephaly and tuberous sclerosis. Acta Neuropathol 98:407–413CrossRefPubMed

Au KS, Hebert AA, Roach ES, Northrup H (1999) Complete inactivation of the TSC2 gene leads to formation of hamartomas. Am J Hum Genet 65:1790–1795CrossRefPubMed

Becker AJ, Urbach H, Scheffler B, Baden T, Normann S, Lahl R, Pannek HW, Tuxhorn I, Elger CE, Schramm J, Wiestler OD, Blumcke I (2002) Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann Neurol 52:29–37CrossRefPubMed

Bourneville D (1880) Sclerose tubereuse des circonvolutions cerebrales: idiotie et epilepsie hemiplegique. Arch Neurol (Paris) 1:81–91

Catania MG, Mischel PS, Vinters HV (2001) Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. J Neuropathol Exp Neurol 60:711–723PubMed

Cepeda C, Hurst RS, Flores-Hernandez J, Hernandez-Echeagaray E, Klapstein GJ, Boylan MK, Calvert CR, Jocoy EL, Nguyen OK, Andre VM, Vinters HV, Ariano MA, Levine MS, Mathern GW (2003) Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia. J Neurosci Res 72:472–486CrossRefPubMed

Crino PB, Chou K (2000) Epilepsy and cortical dysplasias. Curr Treat Options Neurol 2:543–552PubMed

10.

Crino PB, Henske EP (1999) New developments in the neurobiology of the tuberous sclerosis complex. Neurology 53:1384–1390PubMed

11.

Crino PB, Trojanowski JQ, Dichter MA, Eberwine J (1996) Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci USA 93:14152–14157CrossRefPubMed

12.

Crino PB, Miyata H, Vinters HV (2002) Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. Brain Pathol 12:212–233PubMed

13.

Eker R, Mossige J, Johannessen JV, Aars H (1981) Hereditary renal adenomas and adenocarcinomas in rats. Diagn Histopathol 4:99–110PubMed

14.

European CTSC (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 75:1305–1315PubMed

15.

Goldman SA, Luskin MB (1998) Strategies utilized by migrating neurons of the postnatal vertebrate forebrain. Trends Neurosci 21:107–114PubMed

16.

Gomez MR (1999) Definition and criteria for diagnosis. In: Gomez MR, Sampson JR, Whittemore VH (eds) Tuberous sclerosis complex, 3rd edn. Oxford University Press, New York, pp 10–23

17.

Green AJ, Smith M, Yates JR (1994) Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 6:193–196PubMed

18.

Guerreiro MM, Andermann F, Andermann E, Palmini A, Hwang P, Hoffman HJ, Otsubo H, Bastos A, Dubeau F, Snipes GJ, Olivier A, Rasmussen T (1998) Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 51:1263–1269PubMed

19.

Henske EP, Scheithauer BW, Short MP, Wollmann R, Nahmias J, Hornigold N, van Slegtenhorst M, Welsh CT, Kwiatkowski DJ (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 59:400–406PubMed

20.

Henske EP, Wessner LL, Golden J, Scheithauer BW, Vortmeyer AO, Zhuang Z, Klein-Szanto AJ, Kwiatkowski DJ, Yeung RS (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 151:1639–1647PubMed

21.

Hino O, Klein-Szanto AJ, Freed JJ, Testa JR, Brown DQ, Vilensky M, Yeung RS, Tartof KD, Knudson AG (1993) Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci USA 90:327–331PubMed

22.

Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, Hukee MJ, VandenBerg SR, Charlesworth JC (1995) Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. Acta Neuropathol 90:387–399PubMed

23.

Huttenlocher PR (1991) Dendritic and synaptic pathology in mental retardation. Pediatr Neurol 7:79–85CrossRefPubMed

24.

Huttenlocher PR, Wollmann RL (1991) Cellular neuropathology of tuberous sclerosis. Ann N Y Acad Sci 615:140–148PubMed

25.

Johnson MW, Emelin JK, Park SH, Vinters HV (1999) Co-localization of TSC1 and TSC2 gene products in tubers of patients with tuberous sclerosis. Brain Pathol 9:45–54PubMed

26.

Kerfoot C, Wienecke R, Menchine M, Emelin J, Maize JC Jr, Welsh CT, Norman MG, DeClue JE, Vinters HV (1996) Localization of tuberous sclerosis 2 mRNA and its protein product tuberin in normal human brain and in cerebral lesions of patients with tuberous sclerosis. Brain Pathol 6:367–375PubMed

27.

Knudson AG (1993) Antioncogenes and human cancer. Proc Natl Acad Sci USA 90:10914–10921PubMed

28.

Knudson AG (2002) Cancer genetics. Am J Med Genet 111:96–102CrossRefPubMed

29.

Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823PubMed

30.

Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T (1999) Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 59:1206–1211PubMed

31.

Kubo Y, Klimek F, Kikuchi Y, Bannasch P, Hino O (1995) Early detection of Knudson’s two-hits in preneoplastic renal cells of the Eker rat model by the laser microdissection procedure. Cancer Res 55:989–990PubMed

32.

Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda H (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 11:525–534CrossRefPubMed

33.

Lee A, Maldonado M, Baybis M, Walsh CA, Scheithauer B, Yeung R, Parent J, Weiner HL, Crino PB (2003) Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol 53:668–673CrossRefPubMed

34.

Mischel PS, Nguyen LP, Vinters HV (1995) Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 54:137–153PubMed

35.

Mizuguchi M, Takashima S, Yamanouchi H, Nakazato Y, Mitani H, Hino O (2000) Novel cerebral lesions in the Eker rat model of tuberous sclerosis: cortical tuber and anaplastic ganglioglioma. J Neuropathol Exp Neurol 59:188–196

36.

Mizuguchi M, Yamanouchi H, Becker LE, Itoh M, Takashima S (2002) Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia. Acta Neuropathol 104:418–424PubMed

37.

Mizuguchi M, Mori M, Nozaki Y, Momoi MY, Itoh M, Takashima S, Hino O (2004) Absence of allelic loss in cytomegalic neurons of cortical tuber in the Eker rat model of tuberous sclerosis. Acta Neuropathol 107:47–52CrossRefPubMed

38.

Rennebeck G, Kleymenova EV, Anderson R, Yeung RS, Artzt K, Walker CL (1998) 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 95:15629–15634PubMed

39.

Rho JM, Kim DW, Robbins CA, Anderson GD, Schwartzkroin PA (1999) Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet. Epilepsy Res 37:233–240CrossRefPubMed

40.

Richardson EP Jr (1991) Pathology of tuberous sclerosis. Neuropathologic aspects. Ann N Y Acad Sci 615:128–139PubMed

41.

Roach ES, Gomez MR, Northrup H (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624–628PubMed

42.

Scheithauer BW, Reagan TJ (1999) Neuropathology. In: Gomez MR, Sampson JR, Whittemore VH (eds) Tuberous sclerosis complex, 3rd edn. Oxford University Press, New York, pp 101–144

43.

Schwartzkroin PA, Walsh CA (2000) Cortical malformations and epilepsy. Ment Retard Dev Disabil Res Rev 6:268–280CrossRefPubMed

44.

Soucek T, Holzl G, Bernaschek G, Hengstschlager M (1998) A role of the tuberous sclerosis gene-2 product during neuronal differentiation. Oncogene 16:2197–2204PubMed

45.

Sparagana SP, Roach ES (2000) Tuberous sclerosis complex. Curr Opin Neurol 13:115–119CrossRefPubMed

46.

Spreafico R, Battaglia G, Arcelli P, Andermann F, Dubeau F, Palmini A, Olivier A, Villemure JG, Tampieri D, Avanzini G, Avoli M (1998) Cortical dysplasia: an immunocytochemical study of three patients. Neurology 50:27–36PubMed

47.

Stefansson K, Wollman RL, Huttenlocher PR (1999) Lineage of cells in the central nervous system. In: Gomez MR, Sampson JR, Whittemore VH (eds) Tuberous sclerosis complex, 3rd edn. Oxford University Press, New York, pp 251–262

48.

Taylor DC, Falconer MA, Bruton CJ, Corsellis JA (1971) Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:369–387PubMed

49.

Uhlmann EJ, Wong M, Baldwin RL, Bajenaru ML, Onda H, Kwiatkowski DJ, Yamada K, Gutmann DH (2002) Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol 52:285–296CrossRefPubMed

50.

Uhlmann EJ, Apicelli AJ, Baldwin RL, Burke SP, Bajenaru ML, Onda H, Kwiatkowski D, Gutmann DH (2002) Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2^+/− cells. Oncogene 21:4050–4059CrossRefPubMed

51.

Van Slegtenhorst M, Hoogt R de, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, Ouweland A van den, Halley D, Young J, et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808PubMed

52.

Vinters HV, Kerfoot C, Catania M, Emelin JK, Roper SN, DeClue JE (1998) Tuberous sclerosis-related gene expression in normal and dysplastic brain. Epilepsy Res 32:12–23CrossRefPubMed

53.

Wenzel HJ, Cole TB, Born DE, Schwartzkroin PA, Palmiter RD (1997) Ultrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. Proc Natl Acad Sci USA 94:12676–12681CrossRefPubMed

54.

Wolf HK, Normann S, Green AJ, Bakel I von, Blumcke I, Pietsch T, Wiestler OD, Deimling A von (1997) Tuberous sclerosis-like lesions in epileptogenic human neocortex lack allelic loss at the TSC1 and TSC2 regions. Acta Neuropathol 93:93–96CrossRefPubMed

55.

Yamanouchi H, Jay V, Rutka JT, Takashima S, Becker LE (1997) Evidence of abnormal differentiation in giant cells of tuberous sclerosis. Pediatr Neurol 17:49–53PubMed

56.

Yeung RS, Xiao GH, Jin F, Lee WC, Testa JR, Knudson AG (1994) Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci USA 91:11413–11416PubMed

57.

Yeung RS, Xiao GH, Everitt JI, Jin F, Walker CL (1995) Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat. Mol Carcinog 14:28–36PubMed

58.

Yeung RS, Katsetos CD, Klein-Szanto A (1997) Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am J Pathol 151:1477–1486PubMed

Titel: Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis
verfasst von: H. Jürgen Wenzel
Leena S. Patel
Carol A. Robbins
Adriana Emmi
Raymond S. Yeung
Philip A. Schwartzkroin
Publikationsdatum: 01.08.2004
Verlag: Springer-Verlag
Erschienen in: Acta Neuropathologica / Ausgabe 2/2004
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-004-0865-8

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