title: Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb.
abstract: The mechanisms by which early spatiotemporal expression patterns of transcription factors such as Pax6 regulate cortical progenitors in a region-specific manner are poorly understood. Pax6 is expressed in a gradient across the developing cortex and is essential for normal corticogenesis. We found that constitutive or conditional loss of Pax6 increases cortical progenitor proliferation by amounts that vary regionally with normal Pax6 levels. We compared the gene expression profiles of equivalent Pax6-expressing progenitors isolated from Pax6⁺/⁺ and Pax6⁻/⁻ cortices and identified many negatively regulated cell-cycle genes, including Cyclins and Cdks. Biochemical assays indicated that Pax6 directly represses Cdk6 expression. Cyclin/Cdk repression inhibits retinoblastoma protein (pRb) phosphorylation, thereby limiting the transcription of genes that directly promote the mechanics of the cell cycle, and we found that Pax6 inhibits pRb phosphorylation and represses genes involved in DNA replication. Our results indicate that Pax6's modulation of cortical progenitor cell cycles is regional and direct.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
authors.forename: Da
authors.initials: D
authors.lastname: Mi
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Carr
authors.forename: Petrina A
authors.initials: PA
authors.lastname: Georgala
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Huang
authors.forename: Martine N
authors.initials: MN
authors.lastname: Manuel
authors.forename: Emily
authors.initials: E
authors.lastname: Jeanes
authors.forename: Emi
authors.initials: E
authors.lastname: Niisato
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Sansom
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Livesey
authors.forename: Thomas
authors.initials: T
authors.lastname: Theil
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hasenpusch-Theil
authors.forename: T Ian
authors.initials: TI
authors.lastname: Simpson
authors.forename: John O
authors.initials: JO
authors.lastname: Mason
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology*; D047369:Chromatin Immunoprecipitation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000071841:PAX6 Transcription Factor; D051763:PAX7 Transcription Factor / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D001973:Bromodeoxyuridine; D051361:Cyclin-Dependent Kinase 6; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D000071841:PAX6 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C000605732:Pax6 protein, mouse; C497322:Pax7 protein, mouse; C495912:Cdk6 protein, mouse