Transcriptional regulation of neurodevelopmental and metabolic pathways by the psychiatric illness candidate gene NPAS3
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The basic helix-loop-helix PAS domain transcription factor gene NPAS3 is a risk factor for psychiatric disorders. A knockout mouse model also exhibits behavioural and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 aetiopathology immunofluorescent and transcriptomic approaches were used. Npas3 was co-localised with Dcx, but not other neurogenesis markers, in the hippocampal subgranular zone - the site of adult neurogenesis. This implied that NPAS3 might be involved in maturing, rather than proliferating, neuronal precursor cells. Microarray analysis revealed that the transcriptional activities of NPAS3 and its truncated form (C-terminal deletion) in the HEK293 cell line are sensitive to circadian rhythm context. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was one of many NPAS3 target genes also shown to be regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental pathways. The transcriptional repression of multiple glycolytic genes indicated that NPAS3 has a second role in metabolic regulation. This finding was also confirmed by collaboration with a metabolomics research group at the University of Strathclyde. SOX11, a transcription factor known to play a role in neuronal and glial cell differentiation, was shown to be down-regulated by NPAS3. The set of genes targeted by SOX11 and their ontologies were deduced by a microarray analysis in a SOX11 overexpressing HEK293 cell line. Regulated genes include a previously established SOX11 target, known markers of neurogenesis as well as genes implicated in neuropsychiatric disorders. Multiple histone and zinc finger genes are 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. SOX11 may alter localised expression competence and its targets induce a complex programme of chromatin remodelling and downstream gene expression changes to achieve the mature neuronal phenotype. This thesis details how transcription factors are involved in biological processes linked to psychiatric illness. The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of aspects of neurogenesis relevant to mental illness and may explain the innate and medication-induced susceptibility to diabetes reported in psychiatric patients.