Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly.
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.
Crino
Peter B
PB
PENN Epilepsy Center, Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. crinop@mail.med.upenn.edu
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
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