title: Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization.
abstract: BACKGROUND
  Type II focal cortical dysplasias (FCDs) are malformations of cortical development characterised by the disorganisation of the normal neocortical structure and the presence of dysmorphic neurons (DNs) and balloon cells (BCs). The pathogenesis of FCDs has not yet been clearly established, although a number of histopathological patterns and molecular findings suggest that they may be due to abnormal neuronal and glial proliferation and migration processes.In order to gain further insights into cortical layering disruption and investigate the origin of DNs and BCs, we used in situ RNA hybridisation of human surgical specimens with a neuropathologically definite diagnosis of Type IIa/b FCD and a panel of layer-specific genes (LSGs) whose expression covers all cortical layers. We also used anti-phospho-S6 ribosomal protein antibody to investigate mTOR pathway hyperactivation.
  
  
  RESULTS
  LSGs were expressed in both normal and abnormal cells (BCs and DNs) but their distribution was different. Normal-looking neurons, which were visibly reduced in the core of the lesion, were apparently located in the appropriate cortical laminae thus indicating a partial laminar organisation. On the contrary, DNs and BCs, labelled with anti-phospho-S6 ribosomal protein antibody, were spread throughout the cortex without any apparent rule and showed a highly variable LSG expression pattern. Moreover, LSGs did not reveal any differences between Type IIa and IIb FCD.
  
  
  CONCLUSIONS
  These findings suggest the existence of hidden cortical lamination involving normal-looking neurons, which retain their ability to migrate correctly in the cortex, unlike DNs which, in addition to their morphological abnormalities and mTOR hyperactivation, show an altered migratory pattern.Taken together these data suggest that an external or environmental hit affecting selected precursor cells during the very early stages of cortical development may disrupt normal cortical development.
authors.forename: Laura
authors.initials: L
authors.lastname: Rossini
authors.forename: Valentina
authors.initials: V
authors.lastname: Medici
authors.forename: Laura
authors.initials: L
authors.lastname: Tassi
authors.forename: Francesco
authors.initials: F
authors.lastname: Cardinale
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tringali
authors.forename: Manuela
authors.initials: M
authors.lastname: Bramerio
authors.forename: Flavio
authors.initials: F
authors.lastname: Villani
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, Istituto Neurologico "C, Besta", Via Amadeo 42, 20133 Milano, Italy. garbelli.r@istituto-besta.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Garbelli
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000378:metabolism; D004827:Epilepsy; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D065703:Malformations of Cortical Development, Group I / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010296:Parietal Lobe / Q000378:metabolism* / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D055815:Young Adult
chemical_list: C080632:CUX1 protein, human; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D018398:Homeodomain Proteins; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; C539882:NR4A2 protein, human; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012097:Repressor Proteins; D014157:Transcription Factors; D014746:Vimentin; C546842:MTOR protein, human; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D058570:TOR Serine-Threonine Kinases; D010751:Phosphopyruvate Hydratase
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