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SOX11 target genes: implications for neurogenesis and neuropsychiatric illness

  • Li Sha (a1), Rob Kitchen (a1) (a2), David Porteous (a1), Douglas Blackwood (a3), Walter Muir (a3) and Benjamin Pickard (a1) (a4)...


Objective: Deficits in adult and embryonic neurogenesis have been linked with neurological and psychiatric disorders, so it is important to understand the molecular mechanisms underlying this process. SOX11 is a transcription factor known to play a critical role in the regulation of the neuronal and glial differentiation stage of neurogenesis, so we hypothesised that the identification of its target genes would reveal underlying biological processes relevant to disease.

Methods: SOX11 protein was over-expressed in HEK293 cells and transcriptional changes assessed by microarray analysis. Selected candidate genes were further tested for SOX11 activation in quantitative reverse transcriptase PCR studies of HEK293 cells and Western analysis of SH-SY5Y cells.

Results: Regulated genes included a previously established SOX11 target, known markers of neurogenesis, as well as several genes implicated in neuropsychiatric disorders. Immunofluorescence localised several of the genes within the proliferative subgranular zone of the hippocampus. We observed multiple histone and zinc finger genes regulated by SOX11, many of which were located in two clusters on chromosomes 6 and 19. The chromosome 6 cluster lies within a region of the genome showing the strongest genetic association with schizophrenia.

Conclusion: SOX11 appears to regulate a complex programme of chromatin remodelling and downstream gene expression changes to achieve a mature neuronal phenotype. SOX11 target genes are shown to be involved in neurodevelopmental processes important in health and, potentially, disease.


Corresponding author

Benjamin Pickard, Strathclyde Institute of Pharmacy and Biomedical Sciences, The Andrew Hamnett Wing, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. Tel: +44 141 548 4572; Fax: +44 141 552 2562; E-mail:


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1.Bowles, J, Schepers, G, Koopman, P.Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol 2000;227: 239255.
2.Takahashi, K, Yamanaka, S.Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663676.
3.Yu, J, Vodyanik, MA, Smuga-Otto, K et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:19171920.
4.Park, IH, Zhao, R, West, JA et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008;451:141146.
5.Cunningham, DD, Meng, Z, Fritzsch, B, Casey, ES.Cloning and developmental expression of the soxB2 genes, sox14 and sox21, during Xenopus laevis embryogenesis. Int J Dev Biol 2008;52:9991004.
6.Bergsland, M, Werme, M, Malewicz, M, Perlmann, T, Muhr, J.The establishment of neuronal properties is controlled by Sox4 and Sox11. Genes Dev 2006;20:34753486.
7.Jay, P, Goze, C, Marsollier, C et al. The human SOX11 gene: cloning, chromosomal assignment and tissue expression. Genomics 1995;29:541545.
8.Pevny, L, Placzek, M.SOX genes and neural progenitor identity. Curr Opin Neurobiol 2005;15:713.
9.Lo-Castro, A, Giana, G, Fichera, M et al. Deletion 2p25.2: a cryptic chromosome abnormality in a patient with autism and mental retardation detected using aCGH. Eur J Med Genet 2009;52:6770.
10.Pickard, BS, Malloy, MP, Porteous, DJ, Blackwood, DH, Muir, WJ.Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. Am J Med Genet B Neuropsychiatr Genet 2005;136B:2632.
11.Ferreira, MA, O'Donovan, MC, Meng, YA et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40:10561058.
12.Pieper, AA, Wu, X, Han, TW et al. The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc Natl Acad Sci U S A 2005;102:1405214057.
13.Kempermann, G, Krebs, J, Fabel, K.The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatry 2008;21:290295.
14.Reif, A, Fritzen, S, Finger, M, Strobel, A, Lauer, M, Schmitt, A, Lesch, KP.Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006;11:514522.
15.Gentleman, RC, Carey, VJ, Bates, DM et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004;5:R80.
16.Tusher, VG, Tibshirani, R, Chu, G.Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 2001;98:51165121.
17.Carmona-Saez, P, Chagoyen, M, Tirado, F, Carazo, JM, Pascual-Montano, A.GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists. Genome Biol 2007;8:R3.
18.Nogales-Cadenas, R, Carmona-Saez, P, Vazquez, M et al. GeneCodis: interpreting gene lists through enrichment analysis and integration of diverse biological information. Nucleic Acids Res 2009;37:W317W322.
19.Rozen, S, Skaletsky, H.Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000;132:365386.
20.Dracheva, S, McGurk, SR, Haroutunian, V.mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics. J Neurosci Res 2005;79:868878.
21.Pevny, LH, Lovell-Badge, R.Sox genes find their feet. Curr Opin Genet Dev 1997;7:338344.
22.Haslinger, A, Schwarz, TJ, Covic, M, Chichung Lie, D.Expression of Sox11 in adult neurogenic niches suggests a stage-specific role in adult neurogenesis. Eur J Neurosci 2009;29:21032114.
23.Brown, JP, Couillard-Despres, S, Cooper-Kuhn, CM, Winkler, J, Aigner, L, Kuhn, HG.Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 2003;467:110.
24.Pieper, AA, Xie, S, Capota, E et al. Discovery of a proneurogenic, neuroprotective chemical. Cell 142:3951.
25.Wilson, M, Koopman, P.Matching SOX: partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev 2002;12:441446.
26.Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P.Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748752.
27.Stefansson, H, Ophoff, RA, Steinberg, S et al. Common variants conferring risk of schizophrenia. Nature 2009;460:744747.
28.Nagano, T, Yoneda, T, Hatanaka, Y, Kubota, C, Murakami, F, Sato, M.Filamin A-interacting protein (FILIP) regulates cortical cell migration out of the ventricular zone. Nat Cell Biol 2002;4:495501.
29.Kurosawa, N, Chen, GY, Kadomatsu, K, Ikematsu, S, Sakuma, S, Muramatsu, T.Glypican-2 binds to midkine: the role of glypican-2 in neuronal cell adhesion and neurite outgrowth. Glycoconj J 2001;18:499507.
30.Calaora, V, Chazal, G, Nielsen, PJ, Rougon, G, Moreau, H.mCD24 expression in the developing mouse brain and in zones of secondary neurogenesis in the adult. Neuroscience 1996;73:581594.
31.Poncet, C, Frances, V, Gristina, R, Scheiner, C, Pellissier, JF, Figarella-Branger, D.CD24, a glycosylphosphatidylinositol-anchored molecules is transiently expressed during the development of human central nervous system and is a marker of human neural cell lineage tumors. Acta Neuropathol 1996;91:400408.
32.Belvindrah, R, Rougon, G, Chazal, G.Increased neurogenesis in adult mCD24-deficient mice. J Neurosci 2002;22:35943607.
33.Nieoullon, V, Belvindrah, R, Rougon, G, Chazal, G.mCD24 regulates proliferation of neuronal committed precursors in the subventricular zone. Mol Cell Neurosci 2005;28:462474.
34.Katsetos, CD, Legido, A, Perentes, E, Mork, SJ.Class III beta-tubulin isotype: a key cytoskeletal protein at the crossroads of developmental neurobiology and tumor neuropathology. J Child Neurol 2003;18:851866; discussion 867.
35.van Beest, M, Dooijes, D, van De Wetering, M et al. Sequence-specific high mobility group box factors recognize 10-12-base pair minor groove motifs. J Biol Chem 2000;275:2726627273.
36.Tischfield, MA, Baris, HN, Wu, C et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 2010;140:7487.
37.Vincent, JB, Herbrick, JA, Gurling, HM, Bolton, PF, Roberts, W, Scherer, SW. Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. Am J Hum Genet 2000;67:510514.
38.Vincent, JB, Petek, E, Thevarkunnel, S et al. The RAY1/ ST7 tumor-suppressor locus on chromosome 7q31 represents a complex multi-transcript system. Genomics 2002; 80:283294.
39.Li, L, Hung, AC, Porter, AG.Secretogranin II: a key AP-1-regulated protein that mediates neuronal differentiation and protection from nitric oxide-induced apoptosis of neuroblastoma cells. Cell Death Differ 2008;15:879888.
40.Shyu, WC, Lin, SZ, Chiang, MF et al. Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Invest 2008;118:133148.
41.Hakak, Y, Walker, JR, Li, C et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci U S A 2001;98:47464751.
42.Huang, JT, Leweke, FM, Oxley, D et al. Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med 2006;3:e428.

The following Supporting information is available for this article:

Table S1. 932 genes significant by SAM – Significance analysis of microarrays

Table S2. PCR primers used in validation and timecourse QPCR assay. Primers were designed using PRIMER3 []. Specificity of all primers was checked by Blast and BLAT analyses

Table S3. Significantly (SAM) regulated genes, shown in order, that are found within clusters on chromosomes 6 and 19. The two genes highlighted in bold show downregulation, the rest are upregulated. Histones and zinc finger proteins comprise the majority of the list

Additional Supporting information may be found in the online version of this article.

Please note: Wiley-Blackwell Publishing is not responsible for the content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

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Acta Neuropsychiatrica
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  • EISSN: 1601-5215
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