title: Opposing regulation of Sox2 by cell-cycle effectors E2f3a and E2f3b in neural stem cells.
abstract: The mechanisms through which cell-cycle control and cell-fate decisions are coordinated in proliferating stem cell populations are largely unknown. Here, we show that E2f3 isoforms, which control cell-cycle progression in cooperation with the retinoblastoma protein (pRb), have critical effects during developmental and adult neurogenesis. Loss of either E2f3 isoform disrupts Sox2 gene regulation and the balance between precursor maintenance and differentiation in the developing cortex. Both isoforms target the Sox2 locus to maintain baseline levels of Sox2 expression but antagonistically regulate Sox2 levels to instruct fate choices. E2f3-mediated regulation of Sox2 and precursor cell fate extends to the adult brain, where E2f3a loss results in defects in hippocampal neurogenesis and memory formation. Our results demonstrate a mechanism by which E2f3a and E2f3b differentially regulate Sox2 dosage in neural precursors, a finding that may have broad implications for the regulation of diverse stem cell populations.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Julian
authors.forename: Renaud
authors.initials: R
authors.lastname: Vandenbosch
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Pakenham
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Andrusiak
authors.forename: Angela P
authors.initials: AP
authors.lastname: Nguyen
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McClellan
authors.forename: Devon S
authors.initials: DS
authors.lastname: Svoboda
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Alexandre
authors.initials: A
authors.lastname: Blais
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D050699:E2F3 Transcription Factor / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D050699:E2F3 Transcription Factor; C490840:E2f3 protein, mouse; D020033:Protein Isoforms; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse