Skip to main content
NCBI home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;15(3):179–186. doi: 10.1111/j.1750-3639.2005.tb00518.x

Targeted Gene Expression Analysis in Hemimegalencephaly: Activation of β‐Catenin Signaling

Jia Yu 1, Marianna Baybis 1, Allana Lee 1, Guy McKhann II 2, Diane Chugani 3, William J Kupsky 4, Eleonora Aronica 5, Peter B Crino 1,✉
PMCID: PMC8095959  PMID: 16196383

Abstract

Hemimegalencephaly (HMEG) is a developmental brain malformation characterized by unilateral hemispheric enlargement, cytoarchitectural abnormalities, and an association with epilepsy. To define the developmental pathogenesis of HMEG, the expression of 200 cell signaling, growth, angiogenic, and transcription factor genes was assayed in HMEG samples (n = 8) with targeted cDNA arrays. Differential expression of 31 mRNAs across the 4 gene families was identified in HMEG compared with control cortex. Increases in growth and transcription factor genes included JNK‐1, cyclic AMP response element binding protein (CREB), and tuberin mRNAs and decreases included insulin‐like growth factor‐1 (IGF‐1), transforming growth factor β‐3 (TGF‐β3), and NFkB mRNAs. Increased expression of cyclin D1, c‐myc, and WISP‐1 mRNAs in HMEG suggested activation of the Wnt‐1/β‐catenin cascade. Western analysis demonstrated increased levels of non‐phosphorylated β‐catenin, which transcriptionally activates cyclin D1 and c‐myc genes, but reduced levels of Ser33/Ser37/Thr41 phospho‐β‐catenin, which is essential for β‐catenin‐inactivation, in HMEG. Altered expression of 31 mRNAs from 4 gene families in human HMEG may lead to aberrant cell growth and hemispheric enlargement during brain development. Enhanced cyclin D1 and c‐myc transcription likely reflects increased transcriptionally active β‐catenin due to decreased Ser33/Ser37/Thr41 phospho‐β‐catenin and suggests activation of the Wnt‐1/β‐catenin cascade in HMEG.

Full Text

The Full Text of this article is available as a PDF (408.6 KB).

References

  • 1. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. (1997) Beta‐catenin is a target for the ubiquitin‐proteasome pathway. EMBO J 16:3797–3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Arai Y, Edwards V, Becker LE (1999) A comparison of cell phenotypes in hemimegalencephaly and tuberous sclerosis. Acta Neuropathol (Berl) 98:407–413. [DOI] [PubMed] [Google Scholar]
  • 3. Avanzini G, Spreafico R, Cipelletti B, Sancini G, Frassoni C, Franceschetti S, Lavazza T, Panzica F, Acampora D, Simeone A (2000). Synaptic properties of neocortical neurons in epileptic mice lacking the Otx1 gene. Epilepsia 41 Suppl 6:S200–205. [DOI] [PubMed] [Google Scholar]
  • 4. Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, Tsao MS (2001) Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte‐Duclos disease. Nat Genet 29:396–403. [DOI] [PubMed] [Google Scholar]
  • 5. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB (2001). Classification system for malformations of cortical development: update 2001. Neurology 57:2168–2178. [DOI] [PubMed] [Google Scholar]
  • 6. Carreno M, Wyllie E, Bingaman W, Kotagal P, Comair Y, Ruggieri P (2000). Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 57:331–333. [DOI] [PubMed] [Google Scholar]
  • 7. Chenn A, Walsh CA (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365–369. [DOI] [PubMed] [Google Scholar]
  • 8. Chenn A, Walsh CA (2003). Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta‐catenin overexpressing Transgenic Mice. Cereb Cortex 13:599–606. [DOI] [PubMed] [Google Scholar]
  • 9. Cotter D, Honavar M, Lovestone S, Raymond L, Kerwin R, Anderton B, Everall I (1999). Disturbance of Notch‐1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex. Acta Neuropathol (Berl) 98:465–472. [DOI] [PubMed] [Google Scholar]
  • 10. Crino PB, Miyata H, Vinters HVV (2002). Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. Brain Pathol 12:212–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Crino PB, Trojanowski J, Eberwine J (1997) Internexin and nestin in focal cortical dysplasia and hemimegalencephaly as developmental markers. Acta Neuropath 93:619–627. [DOI] [PubMed] [Google Scholar]
  • 12. de Rosa MJ, Secor DL, Barsom M, Fisher RS, Vinters HV (1992) Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol (Berl) 84:250–260. [DOI] [PubMed] [Google Scholar]
  • 13. DeLone DR, Brown WD, Gentry LR (1999). Proteus syndrome: craniofacial and cerebral MRI. Neuroradiology 41:840–843. [DOI] [PubMed] [Google Scholar]
  • 14. Dhamecha RD, Edwards‐Brown MK (2001) Klippel‐Trenaunay‐Weber syndrome with hemimegalencephaly. J Craniofac Surg 12:194–196. [DOI] [PubMed] [Google Scholar]
  • 15. Flores‐Sarnat L (2002) Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 17:373–384. [DOI] [PubMed] [Google Scholar]
  • 16. Frantz GD, Weimann JM, Levin ME, McConnell SK (1994) Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum. J Neurosci 14:5725–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Galluzzi P, Cerase A, Strambi M, Buoni S, Fois A, Venturi C (2002). Hemimegalencephaly in tuberous sclerosis complex. J Child Neurol 17:677–680. [DOI] [PubMed] [Google Scholar]
  • 18. Herman TE, Siegel MJ. Hemimegalencephaly and linear nevus sebaceous syndrome (2001) J Perinatol 21:336–338. [DOI] [PubMed] [Google Scholar]
  • 19. Kacharmina JE, Crino PB, Eberwine J (1999) Preparation of cDNA from single cells and subcellular regions. Methods Enzymol 303:3–18. [DOI] [PubMed] [Google Scholar]
  • 20. Kossoff EH, Vining EP, Pillas DJ, Pyzik PL, Avellino AM, Carson BS, Freeman JM (2003) Hemispherectomy for intractable unihemispheric epilepsy: etiology vs. outcome. Neurology 61:887–890. [DOI] [PubMed] [Google Scholar]
  • 21. Krieglstein K, Strelau J, Schober A, Sullivan A, Unsicker K (2002) TGF‐beta and the regulation of neuron survival and death. J Physiol Paris 96:25–30. [DOI] [PubMed] [Google Scholar]
  • 22. Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, Eberhart CG (2001) Pten regulates neuronal soma size: a mouse model of Lhermitte‐Duclos disease. Nat Genet 29:404–411. [DOI] [PubMed] [Google Scholar]
  • 23. Merks JH, de Vries LS, Zhou XP, Nikkels P, Barth PG, Eng C, Hennekam RC (2003) PTEN hamartoma tumour syndrome: variability of an entity. J Med Genet 40:111–113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Miller JR, Hocking AM, Brown JD, Moon RT (1999). Mechanism and function of signal transduction by the Wnt/β‐catenin and Wnt/Ca2+ pathways. Oncogene 18:7860–7872. [DOI] [PubMed] [Google Scholar]
  • 25. Moon RT, Bowerman B, Boutros M, Perrimon N (2002) The promise and perils of Wnt signaling through beta‐catenin. Science 296:1644–1646. [DOI] [PubMed] [Google Scholar]
  • 26. Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR (2000) Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Dev Brain Res 119:139–153. [DOI] [PubMed] [Google Scholar]
  • 27. O'Leary DD, Nakagawa Y (2002) Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr Opin Neurobiol 12:14–25. [DOI] [PubMed] [Google Scholar]
  • 28. Persad S, Troussard AA, McPhee TR, Mulholland DJ, Dedhar S (2001). Tumor suppressor PTEN inhibits nuclear accumulation of beta‐catenin and T cell/lymphoid enhancer factor 1‐mediated transcriptional activation. J Cell Biol 153:1161–1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Reuss B, von Bohlen und Halbach O (2003) Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 313:139–57. [DOI] [PubMed] [Google Scholar]
  • 30. Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10. [DOI] [PubMed] [Google Scholar]
  • 31. Waite KA, Eng C (2002) Protean PTEN: form and function. Am J Hum Genet 70:829–844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Wingender E, Chen X, Fricke E, Geffers R, Hehl R, Liebich I, Krull M (2001) The TRANSFAC system on gene expression regulation. Nucleic Acids Res 29:281–283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Wodarz A, Nusse R (1998) Mechanisms of Wnt signaling in development. Ann Rev Cell Dev Biol 14:59–88. [DOI] [PubMed] [Google Scholar]
  • 34. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ (2000) WISP‐1 is a Wnt‐1‐ and beta‐catenin‐responsive oncogene. Genes Dev 14:585–95. [PMC free article] [PubMed] [Google Scholar]
  • 35. Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C (2001) Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus‐like syndromes. Lancet 358:210–211. [DOI] [PubMed] [Google Scholar]
  • 36. Zhou XP, Marsh DJ, Hampel H, Mulliken JB, Gimm O, Eng C (2000) Germline and germline mosaic PTEN mutations associated with a Proteus‐like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations, and lipomatosis. Hum Mol Genet 9:765–768. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES