title: Role for Runx1 in the proliferation and neuronal differentiation of selected progenitor cells in the mammalian nervous system.
abstract: 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.
authors.affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4 Canada.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Theriault
authors.forename: Hugh N
authors.initials: HN
authors.lastname: Nuthall
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.forename: Rita
authors.initials: R
authors.lastname: Lo
authors.forename: Fanie
authors.initials: F
authors.lastname: Barnabe-Heider
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.forename: Stefano
authors.initials: S
authors.lastname: Stifani
mesh_terms: 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
chemical_list: 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
references.citation: Blood. 1999 Mar 15;93(6):1817-24
references.pmid: 10068652
references.citation: Development. 1999 Jun;126(11):2563-75
references.pmid: 10226014
references.citation: J Biol Chem. 2000 Jan 7;275(1):530-8
references.pmid: 10617648
references.citation: J Biol Chem. 2000 Jan 7;275(1):651-6
references.pmid: 10617663
references.citation: J Biol Chem. 2000 Feb 4;275(5):3438-45
references.pmid: 10652337
references.citation: Gene. 2000 Mar 21;245(2):223-35
references.pmid: 10717473
references.citation: J Neurosci. 2000 Oct 15;20(20):7648-56
references.pmid: 11027225
references.citation: Mol Cell Biol. 2001 Mar;21(6):1962-72
references.pmid: 11238932
references.citation: Oncogene. 2001 Dec 20;20(58):8342-57
references.pmid: 11840327
references.citation: Mol Cell Neurosci. 2001 Nov;18(5):485-502
references.pmid: 11922140
references.citation: Development. 2002 Apr;129(8):1871-80
references.pmid: 11934853
references.citation: Cancer Cell. 2002 Apr;1(3):213-5
references.pmid: 12086855
references.citation: Nat Med. 2002 Jul;8(7):743-50
references.pmid: 12091906
references.citation: EMBO J. 2002 Jul 1;21(13):3454-63
references.pmid: 12093746
references.citation: Nat Rev Neurosci. 2002 Jul;3(7):517-30
references.pmid: 12094208
references.citation: Nat Rev Cancer. 2002 Jul;2(7):502-13
references.pmid: 12094236
references.citation: Microsc Res Tech. 2002 Aug 1;58(3):176-88
references.pmid: 12203696
references.citation: Nat Neurosci. 2002 Oct;5(10):946-54
references.pmid: 12352981
references.citation: Cell Biol Int. 2003;27(4):315-24
references.pmid: 12788047
references.citation: Mol Cell Biol. 2003 Oct;23(19):6922-35
references.pmid: 12972610
references.citation: Biotech Histochem. 2003 Apr;78(2):57-70
references.pmid: 14533842
references.citation: Cell. 2004 Jan 23;116(2):235-46
references.pmid: 14744434
references.citation: J Biol Chem. 2004 Apr 9;279(15):15678-87
references.pmid: 14747476
references.citation: Exp Neurol. 2004 Apr;186(2):112-23
references.pmid: 15026250
references.citation: Dev Biol. 2004 May 15;269(2):489-504
references.pmid: 15110715
references.citation: J Neurosci. 2004 Jun 23;24(25):5670-83
references.pmid: 15215289
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10343-8
references.pmid: 15240886
references.citation: Mol Cell Biol. 2004 Oct;24(19):8395-407
references.pmid: 15367661
references.citation: Development. 1991 Dec;113(4):1223-30
references.pmid: 1811938
references.citation: J Anat. 1971 Jul;109(Pt 2):243-51
references.pmid: 5558232
references.citation: Neuron. 1995 Jul;15(1):89-103
references.pmid: 7619533
references.citation: Dev Dyn. 1995 May;203(1):61-70
references.pmid: 7647375
references.citation: Neuron. 1994 Aug;13(2):339-52
references.pmid: 8060615
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9
references.pmid: 8622955
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11167-72
references.pmid: 8855327
references.citation: Development. 1997 Apr;124(8):1611-21
references.pmid: 9108377
references.citation: Neuroscience. 1998 Mar;83(1):191-200
references.pmid: 9466409
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14
references.pmid: 9482916
references.citation: Development. 1998 May;125(9):1659-67
references.pmid: 9521904
references.citation: Mol Cell Biol. 1998 May;18(5):2444-54
references.pmid: 9566865