Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers

J. Mariani, R. Favaro, C. Lancini, G. Vaccari, A. L. Ferri, J. Bertolini, D. Tonoli, E. Latorre, R. Caccia, A. Ronchi, S. Ottolenghi, S. Miyagi, A. Okuda, V. Zappavigna, S. K. Nicolis

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6461-6476
Number of pages16
JournalNucleic Acids Research
Volume40
Issue number14
DOIs
Publication statusPublished - Aug 2012

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Telencephalon
Neural Stem Cells
Alleles
Transgenes
Transcription Factors
Stem Cells
Modifier Genes
Neurogenesis
Electrophoretic Mobility Shift Assay
Neuroglia
Transfection
Electrophoresis
Hippocampus
Cell Culture Techniques
Binding Sites
Maintenance
Phenotype
DNA
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Mariani, J., Favaro, R., Lancini, C., Vaccari, G., Ferri, A. L., Bertolini, J., ... Nicolis, S. K. (2012). Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers. Nucleic Acids Research, 40(14), 6461-6476. https://doi.org/10.1093/nar/gks295

Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers. / Mariani, J.; Favaro, R.; Lancini, C.; Vaccari, G.; Ferri, A. L.; Bertolini, J.; Tonoli, D.; Latorre, E.; Caccia, R.; Ronchi, A.; Ottolenghi, S.; Miyagi, S.; Okuda, A.; Zappavigna, V.; Nicolis, S. K.

In: Nucleic Acids Research, Vol. 40, No. 14, 08.2012, p. 6461-6476.

Research output: Contribution to journalArticle

Mariani, J, Favaro, R, Lancini, C, Vaccari, G, Ferri, AL, Bertolini, J, Tonoli, D, Latorre, E, Caccia, R, Ronchi, A, Ottolenghi, S, Miyagi, S, Okuda, A, Zappavigna, V & Nicolis, SK 2012, 'Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers', Nucleic Acids Research, vol. 40, no. 14, pp. 6461-6476. https://doi.org/10.1093/nar/gks295
Mariani J, Favaro R, Lancini C, Vaccari G, Ferri AL, Bertolini J et al. Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers. Nucleic Acids Research. 2012 Aug;40(14):6461-6476. https://doi.org/10.1093/nar/gks295
Mariani, J. ; Favaro, R. ; Lancini, C. ; Vaccari, G. ; Ferri, A. L. ; Bertolini, J. ; Tonoli, D. ; Latorre, E. ; Caccia, R. ; Ronchi, A. ; Ottolenghi, S. ; Miyagi, S. ; Okuda, A. ; Zappavigna, V. ; Nicolis, S. K. / Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers. In: Nucleic Acids Research. 2012 ; Vol. 40, No. 14. pp. 6461-6476.
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