Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia.
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.
Schizophrenia Research Institute, Sydney, Australia.
Jenny
J
Wong
Carlotta E
CE
Duncan
Natalie J
NJ
Beveridge
Maree J
MJ
Webster
Murray J
MJ
Cairns
Cynthia Shannon
CS
Weickert
D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C524941:MIRN17 microRNA, human; C502963:NPAS3 protein, human