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Co-ordinating retinal histogenesis: early cell cycle exit enhances early cell fate determination in the Xenopus retina

Shin-ichi Ohnuma^1,*, Susannah Hopper¹, Kevin C. Wang^1,, Anna Philpott² and William A. Harris^1,

¹ Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
² Department of Oncology, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK
^* Present address: The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
Present address: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA

Author for correspondence (e-mail: harris{at}mole.bio.cam.ac.uk)

Accepted 21 February 2002

The laminar arrays of distinct cell types in the vertebrate retina are built by a histogenic process in which cell fate is correlated with birth order. To explore this co-ordination mechanistically, we altered the relative timing of cell cycle exit in the developing Xenopus retina and asked whether this affected the activity of neural determinants. We found that Xath5, a bHLH proneural gene that promotes retinal ganglion cell (RGC) fate, ( Kanekar, S., Perron, M., Dorsky, R., Harris, W. A., Jan, L. Y., Jan, Y. N. and Vetter, M. L. (1997) Neuron 19, 981-994), does not cause these cells to be born prematurely. To drive cells out of the cell cycle early, therefore, we misexpressed the cyclin kinase inhibitor, p27Xic1. We found that early cell cycle exit potentiates the ability of Xath5 to promote RGC fate. Conversely, the cell cycle activator, cyclin E1, which inhibits cell cycle exit, biases Xath5-expressing cells toward later neuronal fates. We found that Notch activation in this system caused cells to exit the cell cycle prematuely, and when it is misexpressed with Xath5, it also potentiates the induction of RGCs. The potentiation is counteracted by co-expression of cyclin E1. These results suggest a model of histogenesis in which the activity of factors that promote early cell cycle exit enhances the activity of factors that promote early cellular fates.

Key words: Neurogenesis, Gliogenesis, Cell cycle regulation, Notch, Proneural gene, Xenopus laevis, Xath5

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