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Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors

Guillermo Estivill-Torrus^1,*, Helen Pearson^2,*, Veronica van Heyningen², David J. Price^1, and Penny Rashbass^2,3,

¹ Department of Biomedical Sciences, University of Edinburgh Medical School, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
² MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
³ Centre for Developmental Genetics, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK
^* These authors contributed equally to the work

Authors for correspondence (p.rashbass{at}sheffield.ac.uk and dprice{at}ed.ac.uk)

Accepted 24 October 2001

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.

Key words: Cerebral cortex, Cortical plate, Pax6, Small eye, Mouse, Cell cycle, Cell proliferation, Asymmetrical cell division, p27^Kip1, Ventricular zone

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