title: Sox2 and Pax6 maintain the proliferative and developmental potential of gliogenic neural stem cells In vitro.
abstract: Radial-glia-like neural stem (NS) cells may be derived from neural tissues or via differentiation of pluripotent embryonic stem (ES) cells. However, the mechanisms controlling NS cell propagation and differentiation are not yet fully understood. Here we investigated the roles of Sox2 and Pax6, transcription factors widely expressed in central nervous system (CNS) progenitors, in mouse NS cells. Conditional deletion of either Sox2 or Pax6 in forebrain-derived NS cells reduced their clonogenicity in a gene dosage-dependent manner. Cells heterozygous for either gene displayed moderate proliferative defects, which may relate to human pathologies attributed to SOX2 or PAX6 deficiencies. In the complete absence of Sox2, cells exited the cell cycle with concomitant downregulation of neural progenitor markers Nestin and Blbp. This occurred despite expression of the close relative Sox3. Ablation of Pax6 also caused major proliferative defects. However, a subpopulation of cells was able to expand continuously without Pax6. These Pax6-null cells retained progenitor markers but had altered morphology. They exhibited compromised differentiation into astrocytes and oligodendrocytes, highlighting that the role of Pax6 extends beyond neurogenic competence. Overall these findings indicate that Sox2 and Pax6 are both critical for self-renewal of differentiation-competent radial glia-like NS cells.
authors.affiliation: Wellcome Trust Centre for Stem Cell Research and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QR, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gómez-López
authors.forename: Ole
authors.initials: O
authors.lastname: Wiskow
authors.forename: Rebecca
authors.initials: R
authors.lastname: Favaro
authors.forename: Silvia K
authors.initials: SK
authors.lastname: Nicolis
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology / Q000648:ultrastructure; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000502:physiology; D005434:Flow Cytometry; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology; D064231:Nestin; D058953:Neural Stem Cells / Q000502:physiology* / Q000648:ultrastructure; D009457:Neuroglia / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000502:physiology / Q000648:ultrastructure; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D005136:Eye Proteins; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse