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The Journal of Neuroscience, February 23, 2005, 25(8):2050-2061; doi:10.1523/JNEUROSCI.5108-04.2005

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Cellular/Molecular
Role for Runx1 in the Proliferation and Neuronal Differentiation of Selected Progenitor Cells in the Mammalian Nervous System

Francesca M. Theriault,^1,2 Hugh N. Nuthall,^1,2 Zhifeng Dong,^1,2 Rita Lo,^1,2 Fanie Barnabe-Heider,^2,3 Freda D. Miller,^3,4 and Stefano Stifani^1,2

¹Center for Neuronal Survival, Montreal Neurological Institute, ²Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4 Canada, ³Developmental Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, M5G 1X8 Canada, and ⁴Departments of Physiology and Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8 Canada

Neurogenesis requires factors that regulate the decision of dividing progenitors to leave the cell cycle and activate the neuronal differentiation program. It is shown here that the murine runt-related gene Runx1 is expressed in proliferating cells on the basal side of the olfactory epithelium. These include both Mash1+ olfactory receptor neuron (ORN) progenitors and NeuroD+ ORN precursors. Disruption of Runx1 function in vivo does not cause a change in Mash1 expression but leads to a decrease in the number of NeuroD+ neuronal precursors and an increase in differentiated ORNs. These effects result in premature and ectopic ORN differentiation. It is shown further that exogenous Runx1 expression in cultured olfactory neural progenitors causes an expansion of the mitotic cell population. In agreement with these findings, exogenous Runx1 expression also promotes cortical neural progenitor cell proliferation without inhibiting neuronal differentiation. These effects are phenocopied by a chimeric protein containing ETO, the eight twenty one transcriptional repressor, fused to the Runx1 DNA-binding domain, which suggests the involvement of transcription repression mechanisms. Consistent with this possibility, Runx1 represses transcription driven by the promoter of the cell cycle inhibitor p21^{Cip 1} in cortical progenitors. Together, these findings suggest a previously unrecognized role for Runx1 in coordinating the proliferation and neuronal differentiation of selected populations of neural progenitors.

Key words: AML1; neural precursor; NeuroD; olfactory epithelium; Runx1; transcriptional repression

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Received Aug 18, 2004; revised January 12, 2005; accepted January 13, 2005.

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