title: Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers.
abstract: The transcription factor Sox2 is essential for neural stem cells (NSC) maintenance in the hippocampus and in vitro. The transcription factor Emx2 is also critical for hippocampal development and NSC self-renewal. Searching for 'modifier' genes affecting the Sox2 deficiency phenotype in mouse, we observed that loss of one Emx2 allele substantially increased the telencephalic β-geo (LacZ) expression of a transgene driven by the 5' or 3' Sox2 enhancer. Reciprocally, Emx2 overexpression in NSC cultures inhibited the activity of the same transgene. In vivo, loss of one Emx2 allele increased Sox2 levels in the medial telencephalic wall, including the hippocampal primordium. In hypomorphic Sox2 mutants, retaining a single 'weak' Sox2 allele, Emx2 deficiency substantially rescued hippocampal radial glia stem cells and neurogenesis, indicating that Emx2 functionally interacts with Sox2 at the stem cell level. Electrophoresis mobility shift assays and transfection indicated that Emx2 represses the activities of both Sox2 enhancers. Emx2 bound to overlapping Emx2/POU-binding sites, preventing binding of the POU transcriptional activator Brn2. Additionally, Emx2 directly interacted with Brn2 without binding to DNA. These data imply that Emx2 may perform part of its functions by negatively modulating Sox2 in specific brain areas, thus controlling important aspects of NSC function in development.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Mariani
authors.forename: R
authors.initials: R
authors.lastname: Favaro
authors.forename: C
authors.initials: C
authors.lastname: Lancini
authors.forename: G
authors.initials: G
authors.lastname: Vaccari
authors.forename: A L
authors.initials: AL
authors.lastname: Ferri
authors.forename: J
authors.initials: J
authors.lastname: Bertolini
authors.forename: D
authors.initials: D
authors.lastname: Tonoli
authors.forename: E
authors.initials: E
authors.lastname: Latorre
authors.forename: R
authors.initials: R
authors.lastname: Caccia
authors.forename: A
authors.initials: A
authors.lastname: Ronchi
authors.forename: S
authors.initials: S
authors.lastname: Ottolenghi
authors.forename: S
authors.initials: S
authors.lastname: Miyagi
authors.forename: A
authors.initials: A
authors.lastname: Okuda
authors.forename: V
authors.initials: V
authors.lastname: Zappavigna
authors.forename: S K
authors.initials: SK
authors.lastname: Nicolis
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006624:Hippocampus / Q000378:metabolism; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D050809:POU Domain Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D013687:Telencephalon / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D018398:Homeodomain Proteins; D050809:POU Domain Factors; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C527783:Sox2 protein, mouse; C085076:transcription factor Brn-2