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Articles   |    
Effects of Schizophrenia Risk Variation in the NRG1 Gene on NRG1-IV Splicing During Fetal and Early Postnatal Human Neocortical Development
Clare Paterson, Ph.D.; Yanhong Wang, M.D.; Joel E. Kleinman, M.D., Ph.D.; Amanda J. Law, Ph.D.
Am J Psychiatry 2014;171:979-989. doi:10.1176/appi.ajp.2014.13111518
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Dr. Paterson and Dr. Wang contributed equally to this article.

All authors report no financial relationships with commercial interests.

Funded by a NARSAD Young Investigator Award to Dr. Law, funds from the NIMH Intramural Research Program, and NIMH Conte Center grant P50 MH-086383.

From the Department of Psychiatry, University of Colorado, Denver, School of Medicine, Aurora, Colo.; the Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, Intramural Research Program, NIMH, Bethesda, Md.; and the Lieber Institute for Brain Development, Baltimore, Md.

Address correspondence to Dr. Law (amanda.law@ucdenver.edu).

Copyright © 2014 by the American Psychiatric Association

Received November 19, 2013; Revised February 18, 2014; Revised April 03, 2014; Accepted April 10, 2014.

Abstract

Objective  Neuregulin 1 (NRG1) is a multifunctional neurotrophin that mediates neurodevelopment and schizophrenia risk. The NRG1 gene undergoes extensive alternative splicing, and association of brain NRG1 type IV isoform expression with the schizophrenia-risk polymorphism rs6994992 is a potential mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain tissue. The authors investigated the temporal dynamics of transcription of NRG1-IVNV, compared with the major NRG1 isoforms, across human prenatal and postnatal prefrontal cortical development, and they examined the association of rs6994992 with NRG1-IVNV expression.

Method  NRG1 type I–IV and NRG1-IVNV isoforms were evaluated with quantitative real-time polymerase chain reaction in human postmortem prefrontal cortex tissue samples at 14 to 39 weeks gestation and postnatal ages 0–83 years. The association of rs6994992 genotype with NRG1-IVNV expression and the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms were also determined.

Results  Expression of NRG1 types I, II, and III was temporally regulated during prenatal and postnatal neocortical development. NRG1-IVNV was expressed from 16 weeks gestation until age 3. Homozygosity for the schizophrenia risk allele (T) of rs6994992 conferred lower cortical NRG1-IVNV levels. Assays showed that NRG1-IVNV is a novel nuclear-enriched, truncated NRG1 protein resistant to proteolytic processing.

Conclusions  To the authors’ knowledge, this study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging. It identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins.

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FIGURE 1. Temporal Dynamics of NRG1 Type I–IV mRNA Expression in Human Prefrontal Cortex During Fetal Brain Developmenta

a Determined by means of quantitative real-time PCR analysis of postmortem samples. The numbers of samples for each gestational age were as follows: week 14, N=4; week 15, N=3; week 16, N=2; week 17, N=5; week 18, N=12; week 19, N=12; week 20, N=2; week 39, N=1. The data are normalized to the geometric mean of three housekeeping genes (β-actin, GAPDH, PBGD).

FIGURE 2. Temporal Dynamics of NRG1-IVNV mRNA Expression in Human Prefrontal Cortex During Fetal and Postnatal Lifea

a Determined by means of quantitative real-time PCR analysis of postmortem samples.

b The numbers of samples for each gestational age were as follows: week 14, N=4; week 15, N=3; week 16, N=2; week 17, N=5; week 18, N=12; week 19, N=12; week 20, N=2; week 39, N=1. The data are normalized to the geometric mean of three housekeeping genes (β-actin, GAPDH, PBGD).

c The samples were from the dorsolateral prefrontal cortex in postnatal samples ranging in age from 0 to 83 years (N=195). The bars in the graph are inverse to the relative amount of NRG1-IVNV expression; higher bars indicate lower expression since the figure uses cycle threshold (Ct) values. Samples with Ct values greater than 31 were denoted as having undetectable levels and not included in the regression analysis. Absence of detectable NRG1-IVNV expression is observed after 3 years of age and is denoted by the horizontal black bar.

FIGURE 3. Temporal Dynamics of NRG1 Type I–III mRNA Expression in Human Prefrontal Cortex During Postnatal Brain Development and Aginga

a Determined by means of quantitative real-time PCR analysis of postmortem samples from the dorsolateral prefrontal cortex. For panels A–C, N=189. RNA from six samples included in Figure 2B, footnote c, was not available for study. The data are normalized to the geometric mean of three housekeeping genes (β-actin, GAPDH, PBGD).

FIGURE 4. Association Between rs6994992 Genotype and NRG1-IVNV mRNA Expression in Human Prefrontal Cortex During Fetal and Postnatal Lifea

a The rs6994992 is an NRG1 polymorphism associated with risk for schizophrenia. NRG1-IVNV expression was determined by means of quantitative real-time PCR analysis of postmortem samples. Subjects homozygous for the risk allele (T) in both age groups had the lowest level of NRG1-IVNV mRNA expression. Panel B shows normalized expression relative to the C/C genotype (fold change=2–ΔΔCt; Ct is the cycle threshold value).

FIGURE 5. Subcellular Localization of NRG1-IV-β1a and NRG1-IVNV Proteins in Rat Primary Hippocampal Neuronsa

a Rat hippocampal neurons expressing N-terminally c-Myc-tagged human NRG1 isoforms were stained with a c-Myc antibody to determine subcellular protein distribution. NRG1-I-β1 was generated as a positive control for comparison with full-length NRG1-IV-β1a. NRG1-I-β1 and NRG1-IV-β1a proteins are expressed predominantly at the cell membrane and dendritic processes, whereas NRG1-IVNV is highly localized to the nucleus.

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