Role for Runx1 in the proliferation and neuronal differentiation of selected progenitor cells in the mammalian nervous system.
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 p21Cip 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.
Theriault
Francesca M
FM
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4 Canada.
Nuthall
Hugh N
HN
Dong
Zhifeng
Z
Lo
Rita
R
Barnabe-Heider
Fanie
F
Miller
Freda D
FD
Stifani
Stefano
S
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009831:Olfactory Mucosa / Q000166:cytology* / Q000196:embryology; D018034:Olfactory Receptor Neurons / Q000166:cytology* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology* / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
C107844:AML1-ETO fusion protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins; C493726:Runx1 protein, mouse; D014157:Transcription Factors; D004247:DNA
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