title: Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly.
abstract: My laboratory recently demonstrated that there is selective expression of phosphoribosomal S6 protein in balloon cells in focal cortical dysplasia and hemimegalencephaly but no expression of the upstream kinase, phospho-p70S6 kinase. Two proteins activated by phospho-p70S6 kinase, phospho-STAT3 and phospho-4EBP1, were not detected in balloon cells. Using complementary DNA arrays in hemimegalencephaly specimens, we found increased expression of cyclin D1 and c-myc messenger ribonucleic acids (RNAs). Expression of cyclin D1 and c-myc genes is transcriptionally activated by beta-catenin. Western analysis demonstrated increased levels of nonphosphorylated beta-catenin in hemimegalencephalic cortex. Reduced levels of Ser33, Ser37, and Thr41 phospho-beta-catenin, sites known to be phosphorylated by glycogen synthase kinase 3 and to be essential for beta-catenin inactivation, were detected in hemimegalencephaly. Enhanced transcription of cyclin D1 and c-myc messenger RNAs, increased transcriptionally active beta-catenin, and decreased Ser33/Ser37/Thr41 phospho-beta-catenin suggest activation of the Wnt-1/beta-catenin cascade in hemimegalencephaly, which can lead to aberrant cell proliferation and hemispheric enlargement during brain development. Enhanced activation of phospho-S6 and beta-catenin suggests two converging cell pathways that can be pivotal in the pathogenesis of focal cortical dysplasia and hemimegalencephaly.
authors.affiliation: PENN Epilepsy Center, Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. crinop@mail.med.upenn.edu
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases