Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders

Abstract

Objective Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I–IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. Method NRG3 isoform classes I–IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. Results NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Conclusions Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment developme...

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

“…Similarly, in human brain, genomic regions associated with schizophrenia are enriched for genes that show differential isoform usage across neurodevelopment 7 , implicating many schizophrenia-associated risk loci in the regulation of the expression of specific RNA transcripts. Consistent with these findings, examples of associations between psychiatric risk-associated loci and the abundance of novel, alternatively spliced transcripts are beginning to emerge [8][9][10] , complementing numerous reports of altered splicing patterns in the brains of psychiatric cases, compared to controls [11][12][13] .…”

Developmental expression of Neuregulin‐3 in the rat central nervous system

“…Increased levels of Nrg3 led to the opposite result with a decrease in glutamatergic neurotransmission. These observations provide one mechanism to explain how alterations in Nrg3 mRNA levels (Kao et al, ; Paterson et al, ) underlie changes in glutamatergic neurotransmission associated with these pathological conditions (Cappellini et al, ; Gao & Penzes, ).…”

“…Neuregulin-3 (Nrg3) is a member of the neuregulin (Nrg1-4) family of growth factors, which play important roles in the developing and mature nervous system (Birchmeier & Bennett, 2016;Grieco, Holmes, & Xu, 2018;Mei & Nave, 2014;Mei & Xiong, 2008). Nrg3 is of particular interest as it has emerged as a candidate risk gene for several neuropsychiatric disorders including bipolar disorder and schizophrenia (SZ) (Avramopoulos, 2018; P. L. Chen et al, 2009;Hayes et al, 2016;Loos et al, 2014;Paterson et al, 2017). Recent studies have also indicated that Nrg3 plays important roles in cortical development (Bartolini et al, 2017) and glutamatergic neurotransmission (Wang et al, 2018).…”

“…Nrg2 resembles the Ig-like domain containing isoforms of Nrg1, a domain absent from Nrg3 isoforms. Little is known about the alternative splicing of Nrg3 in the rodent, in contrast to its detailed characterization in human (Carteron, Ferrer-Montiel, & Cabedo, 2006;Kao et al, 2010;Paterson et al, 2017;Zeledon et al, 2015). The Nrg3 human transcripts have been categorized into four major types, shown to be dynamically regulated throughout prefrontal cortical development (Paterson et al, 2017).…”

Characterisation and functional predictions of canine long non-coding RNAs

“…Complementary to the previous tissue-specific analysis, this clustering approach allowed us to identify an lncRNA (RLOC_00033166) expressed in all nervous system tissues with a mean TPM = 7.89 but not detected in any other tissues. Interestingly, this lncRNA is transcribed in antisense orientation to the Neuregulin 3 gene (NRG3), which is involved in neuroblast cell differentiation 30…”