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Molecular Pathogenesis of Focal Cortical Dysplasia and Hemimegalencephaly

PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, crinop{at}mail.med.upenn.edu.

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 ßcatenin. Western analysis demonstrated increased levels of nonphosphorylated ß-catenin in hemimegalencephalic cortex. Reduced levels of Ser33, Ser37, and Thr41 phospho-ß-catenin, sites known to be phosphorylated by glycogen synthase kinase 3 and to be essential for ß-catenin inactivation, were detected in hemimegalencephaly. Enhanced transcription of cyclin D₁ and c-myc messenger RNAs, increased transcriptionally active ß-catenin, and decreased Ser33/Ser37/Thr41 phospho-ß-catenin suggest activation of the Wnt-1/ß-catenin cascade in hemimegalencephaly, which can lead to aberrant cell proliferation and hemispheric enlargement during brain development. Enhanced activation of phospho-S6 and ß-catenin suggests two converging cell pathways that can be pivotal in the pathogenesis of focal cortical dysplasia and hemimegalencephaly. (J Child Neurol 2005;20:330—336).

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