title: Early progenitor cell marker expression distinguishes type II from type I focal cortical dysplasias.
abstract: Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathologic features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons, whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, identifying cellular or molecular differences between these lesion types that explains the histologic differences could provide new diagnostic and therapeutic insights. Type II FCDs express nestin, a neuroglial progenitor protein that is modulated in vitro by the stem cell proteins c-Myc, sex-determining region Y-box 2 (SOX2), and Octamer-4 (Oct-4) after activation of mammalian target of rapamycin complex 1 (mTORC1). Because mTORC1 activation has been demonstrated in type II FCDs, we hypothesized that c-Myc, SOX2, and Oct-4 expression would distinguish type II from type I FCDs. In addition, we assayed the expression of progenitor cell proteins forkhead box G1 (FOXG1), Kruppel-like factor 4 (KLF4), Nanog, and SOX3. Differential expression of 7 stem cellproteins and aberrant phosphorylation of2mTORC1 substrates, S6 andS6 kinase 1 proteins, clearly distinguished type II from type I FCDs(n = 10 each). Our results demonstrate new potential pathogenic pathways in type II FCDs and suggest biomarkers for diagnostic pathology in resected epilepsy specimens.
authors.affiliation: PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
authors.forename: Ksenia A
authors.initials: KA
authors.lastname: Orlova
authors.forename: Victoria
authors.initials: V
authors.lastname: Tsai
authors.forename: Marianna
authors.initials: M
authors.lastname: Baybis
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Heuer
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sisodiya
authors.forename: Maria
authors.initials: M
authors.lastname: Thom
authors.forename: Kevin
authors.initials: K
authors.lastname: Strauss
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Storm
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000209:etiology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007223:Infant; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D054220:Malformations of Cortical Development / Q000145:classification* / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011180:Postmortem Changes; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D055747:SOX Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D055747:SOX Transcription Factors; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases