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 histopathological 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 histological 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, SOX2, and Oct-4 following activation of mammalian target of rapamycin complex 1 (mTORC1). Since 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 FOXG1, KLF4, Nanog, and SOX3. Differential expression of 7 stem cell proteins and aberrant phosphorylation of 2 mTORC1 substrates, S6 and S6 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.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…The giant cells in TSC are histologically similar to balloon cells detected in FCD type IIb in that they exhibit an enlarged cell body and opalescent, glassy-appearing, eosinophilic cytoplasm [6]. Both giant cells and balloon cells express cell proteins characteristic of neuroglial progenitor cells such as SOX2, nestin, vimentin, and c-myc, suggesting a failure to differentiate prior to migration into the cortex [137,[191][192][193]; for reviews see [117] and [185]). With the recent advances in both fetal ultrasonography and magnetic resonance imaging, tubers can be detected during the prenatal period in TSC patients [194][195][196].…”

“…Although both FCD II and tubers are characterized by mTOR activation slight differences in the phosphorylation signaling steps have been reported [119]. In contrast, activation of the mTOR pathway has not been reported in FCD type I [117,120,121], supporting the notion that FCD I and FCD II represent two pathogenetically distinct entities.…”

“…Several immunohistochemical studies provide evidence of enhanced mTOR signaling in FCD II with strong expression of the mTOR marker pS6 in dysmorphic neurons and in balloon cell ( [115][116][117], reviewed in [30,118]; Fig. 1j; Fig.…”

“…Although TSC affects different organ systems, central nervous system involvement is common, resulting in developmental delay, neurobehavioral disability (such as autism), and often severe epilepsy [117,180,181]. Genotypephenotype correlation studies suggest that patients with TSC2 mutations may have a more severe neurologic phenotype [182][183][184][185].…”

“…1k-n). Cortical tubers are focal developmental malformations of the cerebral cortex detected as single or multiple lesions in>80 % of patients with TSC, and linked to both epilepsy and neurocognitive disabilities (for reviews see [117] and [188]). Tubers are frequently encountered in temporal and frontal regions, and are characterized histopathologically by dyslamination and heterogeneous cell types, such as dysmorphic neurons, reactive astrocytes, and socalled "giant cells" [185,186,189,190].…”