title: Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway.
abstract: Cortical tubers are developmental brain malformations in the tuberous sclerosis complex (TSC) that cause epilepsy and autism in TSC patients whose pathogenesis is uncertain. Tsc2 null murine neuroepithelial progenitor (NEP) cells display persistent growth when growth factors are withdrawn, express GFAP at high levels, and have reduced expression of a set of early neuronal lineage markers. Tsc2 null NEP cells exhibit aberrant differentiation into giant cells that express both beta III-tubulin and GFAP and that are morphologically similar to giant cells in human tubers. Tsc2 null giant cells and tuber giant cells have similar transcriptional profiles. Tsc2 null NEP cells express high levels of phosphorylated S6kinase, S6, Stat3, and 4E-BP-1, which is reversed by treatment with rapamycin, an inhibitor of mTOR. We conclude that giant cells in human tubers likely result from a complete loss of TSC2 expression and activation of an mTOR pathway during cortical development.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Onda
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Murphey
authors.forename: Luca
authors.initials: L
authors.lastname: Rastelli
authors.forename: Bonnie E
authors.initials: BE
authors.lastname: Gould Rothberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D039642:Eukaryotic Initiation Factors; D005260:Female; D005333:Fetus; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011247:Pregnancy; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D005904:Glial Fibrillary Acidic Protein; D010750:Phosphoproteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C000624653:TSC2 protein, human; D015534:Trans-Activators; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases