title: Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants.
abstract: The transcription factor Sox2 is active in neural stem cells, and Sox2 'knockdown' mice show defects in neural stem/progenitor cells in the hippocampus and eye, and possibly some neurons. In humans, heterozygous Sox2 deficiency is associated with eye abnormalities, hippocampal malformation and epilepsy. To better understand the role of Sox2, we performed in vitro differentiation studies on neural stem cells cultured from embryonic and adult brains of 'knockdown' mutants. Sox2 expression is high in undifferentiated cells, and declines with differentiation, but remains visible in at least some of the mature neurons. In mutant cells, neuronal, but not astroglial, differentiation was profoundly affected. beta-Tubulin-positive cells were abundant, but most failed to progress to more mature neurons, and showed morphological abnormalities. Overexpression of Sox2 in neural cells at early, but not late, stages of differentiation, rescued the neuronal maturation defect. In addition, it suppressed GFAP expression in glial cells. Our results show an in vitro requirement for Sox2 in early differentiating neuronal lineage cells, for maturation and for suppression of alternative lineage markers. Finally, we examined newly generated neurons from Sox2 ;knockdown' newborn and adult mice. GABAergic neurons were greatly diminished in number in newborn mouse cortex and in the adult olfactory bulb, and some showed abnormal morphology and migration properties. GABA deficiency represents a plausible explanation for the epilepsy observed in some of the knockdown mice, as well as in SOX2-deficient individuals.
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavallaro
authors.forename: Jessica
authors.initials: J
authors.lastname: Mariani
authors.forename: Cesare
authors.initials: C
authors.lastname: Lancini
authors.forename: Elisa
authors.initials: E
authors.lastname: Latorre
authors.forename: Roberta
authors.initials: R
authors.lastname: Caccia
authors.forename: Francesca
authors.initials: F
authors.lastname: Gullo
authors.forename: Menella
authors.initials: M
authors.lastname: Valotta
authors.forename: Silvia
authors.initials: S
authors.lastname: DeBiasi
authors.forename: Laura
authors.initials: L
authors.lastname: Spinardi
authors.forename: Antonella
authors.initials: A
authors.lastname: Ronchi
authors.forename: Enzo
authors.initials: E
authors.lastname: Wanke
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Rebecca
authors.initials: R
authors.lastname: Favaro
authors.forename: Sergio
authors.initials: S
authors.lastname: Ottolenghi
authors.forename: Silvia K
authors.initials: SK
authors.lastname: Nicolis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000166:cytology; D064032:Calbindin 2; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D024002:HMGB Proteins / Q000378:metabolism*; D016086:Lentivirus; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D009830:Olfactory Bulb / Q000166:cytology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D055748:SOXB1 Transcription Factors; D013003:Somatosensory Cortex / Q000166:cytology; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015415:Biomarkers; D064032:Calbindin 2; D002843:Chromatin; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D024002:HMGB Proteins; D064030:S100 Calcium Binding Protein G; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D014404:Tubulin; D005680:gamma-Aminobutyric Acid; D004247:DNA