Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia
Open accessAbstract
NPAS3 is a developmentally important transcription factor that has been associated with psychiatric illness. Our aim is to better define the regulation of NPAS3 mRNA (messenger RNA) levels during normal human prefrontal cortical development and in schizophrenia. Utilizing postmortem tissue from 134 human brains, we assessed: 60 normal brains ranging in age from birth to adulthood, 37 chronic individuals with schizophrenia, and 37 matched controls. mRNA and microRNA (miRNA) expressions were measured by microarray and quantitative real-time PCR. Protein expression was measured by Western blotting. During human postnatal cortical development (neonate to adult), we found decreased NPAS3 mRNA yet increased NPAS3 protein expression, suggesting the involvement of posttranscriptional regulation. Through screening, we identified one NPAS-targeted miRNA (miR-17) that changed in a pattern consistent with the developmental regulation of NPAS3. Using luciferase reporter assays, we assessed the impact of miR-17 on NPAS3 translation and demonstrated that miR-17 alters NPAS3 biosynthesis by binding to the NPAS3 3'untranslated region (UTR). In schizophrenia prefrontal cortex, we found significant elevations in miR-17 expression. While NPAS3 mRNA was unaltered, reduced NPAS3 protein expression was detected in a subpopulation of people with schizophrenia. The reciprocal expression of NPAS3 mRNA and protein during postnatal development mediated by a schizophrenia-associated change in miR-17 suggests that there is complex control over NPAS3 synthesis in the human prefrontal cortex and that if NPAS3 is dysregulated in schizophrenia, it is not evident by large changes in NPAS3 expression. Further studies into how changes in NPAS3 or its miRNA regulator may influence the development of schizophrenia are warranted.
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NPAS3 is differentially expressed in the prefrontal cortex of schizophrenia patients.
“It has also been shown that NPAS3 is differentially expressed in the prefrontal cortex of schizophrenia patients (Wong et al. 2013)”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Wong et al. 2013
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“It has also been shown that NPAS3 is differentially expressed in the prefrontal cortex of schizophrenia patients (Wong et al. 2013) and that NPAS3 acts as a master regulator of many neuropsychiatric risk genes (Michaelson et al. 2017).”
Background
- Authors
- Wong, J., Duncan, C. E., Beveridge, N. J., Webster, M. J., Cairns, M. J., & Shannon Weickert, C.
- Affiliations
- Schizophrenia Research Institute (AU)
- Hunter Medical Research Institute (AU)
- Stanley Medical Research Institute (US)
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-01-06
- Volume
- 39
- Issue
- 2
- Pages
- 396-406
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC3576160
- OpenAlex
- W2097697176
- Cited by
- 43
- References
- 28
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 10 · 2013: 2 · 2012: 1
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Schizophrenia Bulletin (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Figshare (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (F32NS070491)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- NPAS3, miR-17
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Nerve Tissue Proteins, RNA, Messenger, Schizophrenia, Transcription Factors, Cohort Studies, Case-Control Studies, Prefrontal Cortex, Gene Expression Regulation, Developmental, RNA Interference, MicroRNAs, Basic Helix-Loop-Helix Proteins, Young Adult, Real-Time Polymerase Chain Reaction
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