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SOX11 target genes: implications for neurogenesis and neuropsychiatric illness

Published online by Cambridge University Press:  24 June 2014

Li Sha ,
Rob Kitchen ,
David Porteous ,
Douglas Blackwood ,
Walter Muir  and
Benjamin Pickard
Li Sha
Affiliation:
Medical Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
Rob Kitchen
Affiliation:
Medical Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK School of Physics, University of Edinburgh, Edinburgh, UK
David Porteous
Affiliation:
Medical Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
Douglas Blackwood
Affiliation:
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
Walter Muir
Affiliation:
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
Benjamin Pickard
Affiliation:
Medical Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK Strathclyde Institute of Pharmacy and Biomedical Sciences, Centre for Neuroscience, University of Strathclyde, Glasgow, UK
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Extract

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.

Keywords

microarray analysisnervous system disorderstranscription factor
Type
Research Article
Information
Acta Neuropsychiatrica , Volume 24 , Issue 1 , February 2012 , pp. 16 - 25
Copyright
Copyright © Cambridge University Press 2011

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Supporting Information

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 [http://workbench.sdsc.edu]. Specificity of all primers was checked by Blast and BLAT analyses http://www.ncbi.nlm.nih.gov/Blast.cgi

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.

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