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Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

Molecular Psychiatry volume 17, pages 267–279 (2012)Cite this article

Abstract

The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone—the site of adult neurogenesis—but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD+, glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients.

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Acknowledgements

We acknowledge Royal Society of Physicians in Edinburgh Sim Fellowship to BSP and a China Council Studentship to LS. SJC was supported in part by a NARSAD Young Investigator Award.

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Author notes

  1. L Sha and L MacIntyre: Equal authorship status.

  2. W J Muir: Deceased.

Authors and Affiliations

  1. Department of Medical Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK

    L Sha, J A Machell & D J Porteous

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

    L MacIntyre, D G Watson & B S Pickard

  3. Pfizer, Pfizer Global Research and Development, Neuroscience Research Unit, Groton, CT, USA

    M P Kelly & N J Brandon

  4. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK

    W J Muir & D H Blackwood

  5. Institute of Membrane and Systems Biology, University of Leeds, Leeds, UK

    S J Clapcote

  6. CeNsUS—Centre for Neuroscience, University of Strathclyde, Glasgow, UK

    B S Pickard

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  1. L Sha
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Correspondence to B S Pickard.

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Sha, L., MacIntyre, L., Machell, J. et al. Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3. Mol Psychiatry 17, 267–279 (2012). https://doi.org/10.1038/mp.2011.73

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