title: Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors.
abstract: In the proliferative zone of the developing cerebral cortex, multipotential progenitors predominate early in development and divide to increase the progenitor pool. As corticogenesis progresses, proportionately fewer progenitors are produced and, instead, cell divisions yield higher numbers of postmitotic neurones or glial cells. As the switch from the generation of progenitors to that of differentiated cells occurs, the orientation of cell division alters from predominantly symmetrical to predominantly asymmetrical. It has been hypothesised that symmetrical divisions expand the progenitor pool, whereas asymmetrical divisions generate postmitotic cells, although this remains to be proved. The molecular mechanisms regulating these processes are poorly understood. The transcription factor Pax6 is highly expressed in the cortical proliferative zone and there are morphological defects in the Pax6(Sey/Sey) (Pax6 null) cortex, but little is known about the principal cellular functions of Pax6 in this region. We have analysed the cell-cycle kinetics, the progenitor cleavage orientation and the onset of expression of differentiation markers in Pax6(Sey/Sey) cortical cells in vivo and in vitro. We showed that, early in corticogenesis at embryonic day (E) 12.5, the absence of Pax6 accelerated cortical development in vivo, shortening the cell cycle and the time taken for the onset of expression of neural-specific markers. This also occurred in dissociated culture of isolated cortical cells, indicating that the changes were intrinsic to the cortical cells. From E12.5 to E15.5, proportions of asymmetrical divisions increased more rapidly in mutant than in wild-type embryos. By E15.5, interkinetic nuclear migration during the cell cycle was disrupted and the length of the cell cycle was significantly longer than normal in the Pax6(Sey/Sey) cortex, with a lengthening of S phase. Together, these results show that Pax6 is required in developing cortical progenitors to control the cell-cycle duration, the rate of progression from symmetrical to asymmetrical division and the onset of expression of neural-specific markers.
authors.affiliation: Department of Biomedical Sciences, University of Edinburgh Medical School, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Estivill-Torrus
authors.forename: Helen
authors.initials: H
authors.lastname: Pearson
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.forename: Penny
authors.initials: P
authors.lastname: Rashbass
mesh_terms: D000818:Animals; D015415:Biomarkers; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D048429:Cell Size; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D005136:Eye Proteins; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011247:Pregnancy; D012097:Repressor Proteins; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D005136:Eye Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C106292:Numbl protein, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors