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Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3
- Source :
- Molecular Psychiatry, Molecular Psychiatry, Nature Publishing Group, 2011, ⟨10.1038/mp.2011.73⟩
- Publication Year :
- 2011
- Publisher :
- HAL CCSD, 2011.
-
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.
- Subjects :
- Transcription, Genetic
SOX transcription factor
Mice
chemistry.chemical_compound
transcriptomics
0302 clinical medicine
Basic Helix-Loop-Helix Transcription Factors
Transcriptional regulation
SOX Transcription Factors
Oligonucleotide Array Sequence Analysis
Mice, Knockout
Neurons
bipolar disorder
0303 health sciences
biology
NPAS3
Neurogenesis
glycolysis
metabolomics
Circadian Rhythm
3. Good health
Psychiatry and Mental health
medicine.medical_specialty
Recombinant Fusion Proteins
Nerve Tissue Proteins
03 medical and health sciences
Cellular and Molecular Neuroscience
Internal medicine
medicine
Animals
Humans
Molecular Biology
Transcription factor
030304 developmental biology
Dihydroxyacetone phosphate
Brain Chemistry
Microarray analysis techniques
Mice, Inbred C57BL
schizophrenia
Metabolic pathway
HEK293 Cells
Endocrinology
chemistry
Dentate Gyrus
biology.protein
Energy Metabolism
Transcriptome
Transcription Factor Gene
030217 neurology & neurosurgery
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 13594184 and 14765578
- Database :
- OpenAIRE
- Journal :
- Molecular Psychiatry, Molecular Psychiatry, Nature Publishing Group, 2011, ⟨10.1038/mp.2011.73⟩
- Accession number :
- edsair.doi.dedup.....af4edb603dbd6b596e955e8242659186