Abstract
Balloon cells (BCs) in focal cortical dysplasia (FCD) and giant cells (GCs) in tubers of the tuberous sclerosis complex (TSC) share phenotypic similarities. TSC1 or TSC2 gene mutations in TSC lead to mTOR pathway activation and p70S6kinase (phospho-S6K) and ribosomal S6 (phospho-S6) protein phosphorylation. Phospho-S6K, phospho-S6, and phospho-S6K-activated proteins phospho-STAT3 and phospho-4EBP1 were detected immunohistochemically in GCs, whereas only phospho-S6 was observed in BCs. Expression of four candidate gene families (cell signaling, cell adhesion, growth factor/receptor, and transcription factor mRNAs) was assayed in single, microdissected phospho-S6-immunolabeled BCs and GCs as a strategy to define whether BCs and GCs exhibit differential transcriptional profiles. Among 60 genes, differential expression of 24 mRNAs distinguished BCs from GCs and only 4 genes showed similar expression profiles between BCs and GCs. Tuberin mRNA levels were reduced in GCs from TSC patients with TSC2 gene mutations but were unchanged in BCs. Phospho-S6K, -S6, -STAT3, and -4EBP1 expression in GCs reflects loss of hamartin-tuberin-mediated mTOR pathway inhibition. Phospho-S6 expression alone in BCs does not support mTOR cascade activation in FCD. Differential gene expression profiles in BCs and GCs supports the hypothesis that these cell types derive by distinct pathogenic mechanisms.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adolescent
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Adult
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Cell Count / methods
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology*
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Child
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Child, Preschool
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DNA-Binding Proteins / metabolism
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Epilepsy / genetics
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Epilepsy / metabolism
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Epilepsy / pathology*
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Eukaryotic Initiation Factors / metabolism
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Female
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Gene Expression Regulation
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Humans
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Immunohistochemistry / methods
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In Situ Hybridization / methods
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Infant
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Insulin-Like Growth Factor II / genetics
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Insulin-Like Growth Factor II / metabolism
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Male
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Microdissection / methods
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Kinases / physiology
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Ribosomal Protein S6 / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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STAT3 Transcription Factor
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TOR Serine-Threonine Kinases
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Trans-Activators / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Tuberous Sclerosis / genetics
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Tuberous Sclerosis / metabolism
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Tuberous Sclerosis / pathology*
Substances
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DNA-Binding Proteins
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Eukaryotic Initiation Factors
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RNA, Messenger
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Ribosomal Protein S6
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Transforming Growth Factor beta
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Insulin-Like Growth Factor II
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Protein Kinases
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MTOR protein, human
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases