Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: NRG1
Cytogenetic location: 8p12 Genomic coordinates (GRCh38): 8:31,639,245-32,774,046 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p12 | {?Schizophrenia, susceptibility to} | 603013 | 1 |
The NRG1 gene encodes neuregulin-1, a signaling protein that mediates cell-cell interactions and plays a critical role in the growth of organ systems (Tan et al., 2007).
Neuregulin, also known as heregulin or NEU differentiation factor (NDF), was first identified by Holmes et al. (1992) as a ligand for the NEU/ERBB2 protooncogene (164870). NEU/ERBB2 is closely related to epidermal growth factor receptor (EGFR; 131550) but binds none of the EGFR ligands. Splice variants of heregulin, referred to as heregulin-betas, were also identified.
By screening a human breast adenocarcinoma cDNA library, Holmes et al. (1992) isolated clones corresponding to NRG1, which they called HRG. The clones encoded deduced proteins of 640, 645, 637, and 231 amino acids, which were designated proHRG-alpha, proHRG-beta-1, proHRG-beta-2, and proHRG-beta-3, respectively. Holmes et al. (1992) characterized the differences between the 4 HRGs at the amino acid level. The mature HRGs were estimated to range in size from 228 to 241 amino acids with a predicted molecular mass of about 26 kD. Posttranslational modification occurring at predicted glycosylation sites likely accounts for the observed molecular mass of 45 kD. Northern blot analysis detected mRNA transcripts of 6.6, 2.5, and 1.8 kb in multiple human tissues, but expression was often tissue-specific for 1 of the mRNA transcripts.
Meyer et al. (1997) noted that alternative splicing of the NRG1 gene results in transcripts encoding 3 major isoforms with distinct domain structures, although all contain an EGF-like domain. Type I NRG1, also known as heregulin or NDF, contains an N-terminal immunoglobulin (Ig)-like domain prior to the EGF-like domain, which is followed by a specific hydrophobic stretch and a unique C-terminal domain. The EGF-like domain in type I NRG1 can be either the alpha or beta variant, depending on whether the transcript includes exon 7 or 8, respectively. Type II NRG1, or glial growth factor-2 (GGF2), contains an N-terminal signal peptide, a Kringle-like domain, and an Ig-like domain prior to the EGF-like domain (beta variant). Type III NRG1, or sensory and motor neuron-derived factor (SMDF), contains a unique N terminus with a hydrophobic stretch prior to the EGF-like domain (beta variant). By in situ hybridization of mouse embryos using probes specific for transcripts encoding the 3 major NRG1 isoforms, Meyer et al. (1997) found that type I Nrg1 was expressed predominantly in early mouse embryogenesis, whereas type II and type III were first detected at midgestation. Type I Nrg1 was expressed predominantly in neural tissue, respiratory epithelium, and endocardium. Yolk sac and other embryonic sites also expressed type I Nrg1. Type II Nrg1 was expressed in neural tissues, pituitary, retinal ganglion cell layer, and skeletal muscle. Type III Nrg1 was expressed in neural tissues, olfactory epithelium, and retinal ganglion cell layer, with low expression in endocardium.
By RT-PCR and 5-prime RACE of adult and fetal human brain cDNA libraries, Steinthorsdottir et al. (2004) identified 10 alternatively spliced NRG1 transcripts. They identified an additional variant by database analysis. The transcripts encode proteins with 6 different N-terminal domains and variability in the spacer region downstream of the Ig-like domain. Steinthorsdottir et al. (2004) proposed that the proteins with the 3 novel N-terminal domains be designated types IV, V, and VI NRG1.
Tan et al. (2007) stated that at least 15 NRG1 isoforms are generated through alternative promoter use and splicing. They isolated a full-length clone for NRG1 type IV from adult and fetal human brain cDNA libraries. The deduced 590-residue protein, designated type IV-beta-1a, has a calculated molecular mass of 66 kD. The 1.8-kb transcript contains 11 exons and yields a protein with an Ig-like domain, an EGFc domain, a beta-1 stalk, a transmembrane domain, and a cytoplasmic a-tail, consistent with the beta-1a NRG1 subclass. Several splice variants were identified. NRG1 type IV was detected only in human brain and was 3.5-fold more abundant in fetal brain compared to adult brain, suggesting a role in brain development. NRG1 type IV was not detected in breast tumor or neuroblastoma cell lines.
Steinthorsdottir et al. (2004) determined that the NRG1 gene contains 21 alternatively spliced exons and spans more than 1.1 Mb. Alternative splicing can produce at least 9 alternative promoters upstream of the protein-coding sequences. Most of the exons are located in a 200-kb region at the 3-prime end of the gene.
By in situ hybridization of a tritium-labeled probe to human metaphase spreads, Orr-Urtreger et al. (1993) localized the NDF gene to 8p21-p12. Lee and Wood (1993) localized the HGL gene to 8p22-p11 by PCR experiments involving human/rodent cell hybrids containing a portion of chromosome 8. Thomas et al. (1993) excluded HRG as the site of the mutation in Werner syndrome (277700) by demonstrating recombination in linkage studies.
In mouse embryos 14.5 days postcoitum, Orr-Urtreger et al. (1993) found that NDF expression is confined predominantly to the central and peripheral nervous systems, including the neuroepithelium that lines the lateral ventricles of the brain, the ventral horn of the spinal cord, and the intestinal as well as dorsal root ganglia.
Ozaki et al. (1997) found that a neuregulin-beta isoform increased expression of the NR2C (138254) subunit of the NMDA receptor in cultured mouse cerebellar slices and that this upregulation also required synaptic activity by NMDA receptors. The findings suggested that neuregulins regulate the composition of neurotransmitter receptors in maturing synapses in the brain.
Heregulin is also known as glial growth factor-2 (GGF2), or neuregulin. GGF2 is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system. Cannella et al. (1998) examined the effect of recombinant human GGF2 (rhGGF2) on clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis in the mouse, a major animal model for multiple sclerosis (126200). Clinically, rhGGF2 treatment delayed signs and decreased severity of the disorder, and resulted in statistically significant reductions in relapse rate. The groups treated with rhGGF2 displayed central nervous system lesions with more remyelination than did controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the central nervous system of a regulatory cytokine, interleukin-10 (IL10; 124092), at both the RNA and protein levels. Cannella et al. (1998) concluded that rhGGF2 treatment may represent a novel approach to the management of multiple sclerosis.
Wolpowitz et al. (2000) stated that NRG1 is a member of a family of structurally related glycoproteins that includes NRG2 (603818), NRG3 (605533), and NRG4 (610894). Alternative splicing of at least 15 exons generates a minimum of 14 NRG1 isoforms. These isoforms can be subdivided into 2 mutually exclusive categories: type I (with cytoplasmic tail) and type II (without cytoplasmic tail) isoforms contain an immunoglobulin (Ig)-like domain and are referred to as Ig-NRGs; type III isoforms (with or without cytoplasmic tail) contain a cysteine-rich domain (CRD) N terminal to a common epidermal growth factor (EGF; 131530)-like sequence and are referred to as CRD-NRGs.
Fernandez et al. (2000) demonstrated that neuregulin supports the survival of purified oligodendrocytes and aged oligodendrocyte precursor cells but not of young oligodendrocyte precursor cells. Fernandez et al. (2000) further showed that axons promote the survival of purified oligodendrocytes and that this effect is inhibited if neuregulin is neutralized. In the developing rat optic nerve, delivery of NRG decreases both normal oligodendrocyte death and extra oligodendrocyte death induced by nerve transection, whereas neutralization of endogenous NRG increases the normal death. The authors suggested that NRG is an axon-associated survival signal for developing oligodendrocytes.
Martinou et al. (1991) found that acetylcholine receptor-inducing activity (Aria), a 42-kD glycoprotein purified on the basis of its ability to increase the synthesis of acetylcholine receptors in chick myotubes, increases epsilon-subunit mRNA levels up to 10-fold. Thus, Aria appears to be responsible in a major way for the switch from gamma subunits (100730) to epsilon subunits (100725) in the pentameric acetylcholine receptor protein complex. Falls et al. (1993) purified and cloned a cDNA encoding chick Aria, which is 81% identical to NRG1. They suggested that Aria and Aria-activated tyrosine kinases are important in the differentiation of the neuromuscular junction and perhaps interneuronal synapses as well.
Neuregulins and their receptors, the ERBB protein tyrosine kinases, are essential for neuronal development. Huang et al. (2000) reported that ERBB4 (600543) is enriched in the postsynaptic density and associates with PSD95 (602887). Heterologous expression of PSD95 enhanced NRG activation of ERBB4 and MAP kinase (see 176948). Conversely, inhibiting expression of PSD95 in neurons attenuated NRG-mediated activation of MAP kinase. PSD95 formed a ternary complex with 2 molecules of ERBB4, suggesting that PSD95 facilitates ERBB4 dimerization. Finally, NRG suppressed induction of long-term potentiation in the hippocampal CA1 region without affecting basal synaptic transmission. Thus, NRG signaling may be synaptic and regulated by PSD95. Huang et al. (2000) concluded that a role of NRG signaling in the adult central nervous system may be modulation of synaptic plasticity. Garcia et al. (2000) also found that ERBB4 and PSD95 coimmunoprecipitated from rat forebrain lysates and that the direct interaction was mediated through the C-terminal end of ERBB4. Immunofluorescent studies of cultured rat hippocampal cells showed that ERBB4 colocalized with PSD95 and NMDA receptors at interneuronal postsynaptic regions. The findings suggested that certain ERBB receptors physically interact with membrane-associated guanylate kinases (MAGUKs) in coupling neurotransmitter receptors to intracellular signaling pathways, which may be important in activity-dependent synaptic plasticity.
ERBB4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding its ligand heregulin or activation of protein kinase C (see 176960) by TPA, the ERBB4-ectodomain is cleaved by a metalloprotease. Ni et al. (2001) reported a subsequent cleavage by gamma-secretase that releases the ERBB4 intracellular domain from the membrane and facilitates its translocation to the nucleus. Gamma-secretase cleavage was prevented by chemical inhibitors or a dominant-negative presenilin (104311). Inhibition of gamma-secretase also prevented growth inhibition by heregulin. Ni et al. (2001) concluded that gamma-secretase cleavage of ERBB4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.
Buonanno and Fischbach (2001) provided a detailed review of neuregulins and ERBB receptor signaling pathways in the nervous system.
Vermeer et al. (2003) showed that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from ERBB2 (164870), ERBB3 (190151), and ERBB4, which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates ERBB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes (polarized), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.
Michailov et al. (2004) used mutant and transgenic mice to show that axonal Nrg1 signals information about axon size to Schwann cells. Reduced Nrg1 expression caused hypomyelination and reduced nerve conduction velocity. Neuronal overexpression of Nrg1 induced hypermyelination and demonstrated that Nrg1 type III is the responsible isoform. Michailov et al. (2004) suggested a model by which myelin-forming Schwann cells integrate axonal Nrg1 signals as a biochemical measure of axon size.
Bao et al. (2004) found that sound-induced synaptic activity in the mouse cochlea increased the level of nuclear Nrg-ICD (intracellular domain) and upregulated PSD95 in postsynaptic spiral ganglion neurons. Nrg-ICD enhanced the transcriptional activity of the PSD95 promoter by binding to Eos (606239), a zinc finger transcription factor. The findings identified a molecular basis for activity-dependent synaptic plasticity.
Flames et al. (2004) found that specific mouse Nrg1 isoforms had different effects on the adhesion and migration of primary mouse medial ganglionic eminence-derived neurons. They showed that the membrane-bound type III isoform acted as a substrate for cell adhesion, while the soluble and diffusible types I and II isoforms were chemoattractive and induced cell migration.
Lemmens et al. (2004) found that the alpha and beta isoforms of NRG1 induced a negative inotropic effect in isolated rabbit papillary muscles and a rightward shift in the dose-response curve to isoproterenol. Both effects were attenuated by a nitric oxide synthase (NOS) inhibitor. In cultured rat cardiomyocytes, NRG1-beta enhanced nitrite production and resulted in phosphorylation of endothelial NOS (NOS3; 163729) and the serine/threonine kinase Akt (see AKT1; 164730). Lemmens et al. (2004) concluded that NRG1 has negative inotropic effects and activates endothelial NOS in cardiomyocytes.
Lopez-Bendito et al. (2006) found that development of the mouse thalamocortical projection, one of the most prominent tracts in forebrain, depended on early tangential migration of GABAergic neurons from the lateral to the medial ganglionic eminence. This migration was essential to form a permissive corridor for thalamocortical axons (TCAs) to navigate through the telencephalon. Erbb4 and 2 different Nrg1 isoforms, CRD-Nrg1 and Ig-Nrg1, controlled the guidance of TCAs in the telencephalon.
Ky et al. (2009) quantified serum NRG1-beta in 899 patients with systolic heart failure representing a broad spectrum of disease and found that circulating NRG1-beta was significantly elevated in patients with more severe disease (p = 0.002). In various adjusted models factoring for demographics, NRG1-beta covariates, and potential confounders, NRG1-beta was independently associated with an increased risk of death or cardiac transplantation (p values ranging from 0.02 to 0.04). Associations between NRG1-beta levels and adverse outcomes were most evident in patients with ischemic heart failure compared to patients with nonischemic failure (interaction p = 0.008) and in patients with more advanced disease (New York Heart Association class III/IV) compared to class I/II patients (interaction p = 0.01). These findings were all independent of brain natriuretic peptide (BNP; 600295). Ky et al. (2009) concluded that NRG1-beta is independently associated with heart failure severity and risk of death or cardiac transplantation.
Combining avian blood vessel-specific gene manipulation and mouse genetics, Saito et al. (2012) addressed a long-standing question of how neural crest cells generate sympathetic and medullary lineages during embryogenesis. They found that the dorsal aorta acts as a morphogenetic signaling center that coordinates neural crest cell migration and cell lineage segregation. Bone morphogenetic proteins (BMPs) produced by the dorsal aorta are critical for the production of the chemokine stromal cell-derived factor-1 (SDF1; 600835) and neuregulin-1 in the paraaortic region, which act as chemoattractants for early migration. Later, BMP signaling is directly involved in the sympathomedullary segregation. Saito et al. (2012) concluded that their study provided insights into the complex developmental signaling cascade that instructs one of the earliest events of neurovascular interactions guiding embryonic development.
Early social isolation results in adult behavioral and cognitive dysfunction that correlates with white matter alterations. Makinodan et al. (2012) showed that mice isolated for 2 weeks immediately after weaning have alterations in prefrontal cortex function and myelination that do not recover with reintroduction into a social environment. These alterations, which occur only during this critical period, are phenocopied by loss of oligodendrocyte ErbB3 (190151) receptors, and social isolation leads to reduced expression of the ErbB3 ligand neuregulin-1. Makinodan et al. (2012) concluded that social experience regulates prefrontal cortex myelination through neuregulin-1/ErbB3 signaling and that this is essential for normal cognitive function, thus providing a cellular and molecular context to understand the consequences of social isolation.
Possible Role in Schizophrenia
Hahn et al. (2006) found that postmortem tissue slices of prefrontal cortex obtained from patients with schizophrenia (181500) demonstrated significantly increased NRG1-induced activation of ERBB4 compared to controls despite similar levels of the 2 proteins. Tissue from schizophrenia subjects also showed increases in ERBB4-PSD95 interactions although this finding was independent of ERBB4 stimulation. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects compared to controls, consistent with enhanced NRG1-ERBB4 signaling. The findings were consistent with the hypothesis that NMDA receptor hypofunction may play a role in schizophrenia. An Editorial Expression of Concern has been published regarding the Western blot images presented in some of the figures in the article by Hahn et al. (2006).
Using human constructs and RNA interference against endogenous rat proteins, Li et al. (2007) demonstrated that the ERBB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity led to the activation and recruitment of ERBB4 into the synapse. Overexpressed ERBB4 selectively enhanced AMPA synaptic currents and increased dendritic spine size. Preventing NRG1/ERBB4 signaling destabilized synaptic receptors and led to loss of synaptic NMDA currents and spines. Li et al. (2007) concluded that normal activity-driven glutamatergic synapse development is impaired by genetic defects in NRG1/ERBB4 signaling leading to glutaminergic hypofunction. These findings linked proposed effectors in schizophrenia: NRB1/ERBB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.
Woo et al. (2007) showed that Erbb4 localized at GABAergic terminals of rat prefrontal cortex. Studies using the endogenous rodent protein and an exogenous human construct indicated a role for NRG1 in regulation of GABAergic transmission. This effect was blocked by inhibition or mutation of rodent Erbb4, suggesting the involvement of ERBB4. Taken together, the results indicated that NRG1 regulates GABAergic transmission via presynaptic ERBB4 receptors, identifying a novel function of NRG1. Woo et al. (2007) suggested that since both NRG1 and ERBB4 have emerged as susceptibility genes of schizophrenia, these observations may indicate a mechanism for abnormal GABAergic neurotransmission in that disorder.
Fazzari et al. (2010) showed that Nrg1 and ErbB4 (600543) signaling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA-containing interneurons. In contrast to the view that supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, Fazzari et al. (2010) found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin (168890)-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrated that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Fazzari et al. (2010) concluded that Nrg1 and ErbB4 signaling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the etiology of schizophrenia.
NMDAR hypofunction is considered a key detrimental consequence of excessive NRG1-ErbB4 signaling found in people with schizophrenia. Using whole cell recordings of mouse hippocampal slices, Pitcher et al. (2011) found that Nrg1-beta-ErbB4 signaling blocked Src (190090) kinase-induced enhancement of NMDAR excitatory currents. However, this signaling pathway did not affect basal NMDAR function. Similar results were observed in pyramidal cells in the prefrontal cortex. Nrg1-beta also prevented long-term potentiation of synaptic transmission induced by theta-burst stimulation. The study identified Src as a downstream target of the Nrg1-beta-ErbB4 signaling pathway, and indicated that Src activity is an essential step in regulating synaptic plasticity.
Del Monte-Nieto et al. (2018) presented a model of trabeculation in mice that integrated dynamic endocardial and myocardial cell behaviors and extracellular matrix (ECM) remodeling, and revealed epistatic relationships between the involved signaling pathways. Notch1 (190198) signaling promotes extracellular matrix degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas Nrg1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through Nrg1 control of Vegfa (192240), but act antagonistically to establish trabecular architecture. Del Monte-Nieto et al. (2018) concluded that their findings enabled the prediction of persistent extracellular matrix and cardiomyocyte growth in a mouse noncompaction cardiomyopathy model, providing insights into the pathophysiology of congenital heart disease.
By a genomewide scan of schizophrenia (181500) families in Iceland, Stefansson et al. (2002) showed that a schizophrenia locus maps to chromosome 8p, as had been suggested by previous work done in 5 populations (see 603013). Extensive fine mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identified NRG1 as a candidate gene for schizophrenia. Stefansson et al. (2002) pointed out that NRG1 is expressed at CNS synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors.
Stefansson et al. (2003) presented information supporting the association of neuregulin-1 in schizophrenia in a Scottish population. They genotyped markers representing a core at-risk haplotype found in Icelanders at the 5-prime end of the NRG1 gene in 609 unrelated Scottish patients and 618 unrelated Scottish control subjects. The frequency of the 7-marker haplotype among the Scottish patients was significantly greater than that among the control subjects (10.2% vs 5.9%, P = 0.00031). The estimated risk ratio was 1.8, which was in keeping with the finding in unrelated Icelandic patients (2.1).
In a case-control and family-based association study of the NRG1 gene and schizophrenia in Han Chinese, Zhao et al. (2004) found no association of schizophrenia with the haplotype identified by Stefansson et al. (2002, 2003) in Icelandic and Scottish populations. They did, however, identify another haplotype to be significantly associated with schizophrenia in both case-control (p = 0.0057) and TDT analyses (p = 0.0043).
Li et al. (2004) investigated a Han Chinese population using both a family trio design and a case control design to determine if NRG1 is associated with schizophrenia in Asian populations. They genotyped 25 microsatellite markers and SNPs spanning the NRG1 gene, including markers of the 7-marker haplotype found in excess in Icelandic and Scottish schizophrenia subjects. Li et al. (2004) identified 2 different haplotypes at the 5-prime end of the gene and a third at the 3-prime end of the gene that were potentially associated with schizophrenia in the Chinese population. However, none of these haplotypes was significantly associated with schizophrenia after correcting for multiple testing. Li et al. (2004) concluded that the NRG1 gene may be associated with schizophrenia in Han Chinese, but the haplotype differs from that found in Icelandic and Scottish schizophrenic patients.
To determine if the underlying cause of the association discrepancies between schizophrenia and polymorphisms in the NRG1 gene might be due to population-specific genetic variation, Gardner et al. (2006) typed 13 SNPs across NRG1, including 2 of the SNPs originally associated with schizophrenia in the Icelandic population, in 1,088 individuals from 39 populations. Most of the SNPs analyzed displayed differing frequencies according to geographic areas. These differences were especially relevant in 2 SNPs located in a large intron of the gene, which revealed genetic stratification related to broad continental areas. Furthermore, haplotype analysis revealed a clear clustering according to geographic areas. Gardner et al. (2006) cautioned that this population diversity must be taken into account to clarify the putative role of the NRG1 gene in susceptibility to schizophrenia.
Go et al. (2005) performed linkage analysis on an NIMH Alzheimer disease sample and demonstrated a specific linkage peak for Alzheimer disease (AD; 104300) with psychosis on 8p12, which encompasses the NRG1 gene. The authors also demonstrated a significant association between an NRG1 SNP (rs3924999) and AD with psychosis (chi-square = 7.0; P = 0.008). This SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with the phenotype. Go et al. (2005) suggested that NRG1 plays a role in increasing the genetic risk for positive symptoms of psychosis in a proportion of late-onset Alzheimer disease families.
Tan et al. (2007) demonstrated that a T-C SNP (rs6994992) in 5-prime promoter region of the NRG1 gene, which has been associated with schizophrenia (see Stefansson et al., 2002; Li et al., 2004), is a functional promoter variant that regulates expression of the NRG1 type IV isoform. The T allele, which is the schizophrenia risk allele, showed a 65% increase in promoter activity.
Meyer et al. (1997) found that targeted disruptions eliminating the expression of specific Nrg1 isoforms in mice produced distinct phenotypes. Type I Nrg1 was required for generation of neural crest-derived neurons in cranial ganglia and for trabeculation of the heart ventricle, whereas type III Nrg1 was required for early development of Schwann cells.
Mice homozygous for disruptions of all NRG1 isoforms, all Ig-NRG1 isoforms, and all cytoplasmic tail-containing isoforms die at embryonic day 10.5 from cardiac defects. In particular, these mice die before significant expression of CRD-NRG1 isoforms, which predominate after midgestation. By histologic analyses, Wolpowitz et al. (2000) found that homozygous CRD-NRG1-deficient mice had normal neuronal trajectory and outgrowth, but that the projections defasciculated, branched abnormally, and failed to sustain peripheral neuromuscular synaptic development. Newborn mutants had immature skeletal muscle. Schwann cells were generated in the mutants but failed to survive, consistent with the designation of NRG1 as a Schwann cell survival factor. Schwann cells in turn appeared to provide trophic support only after the nerve had entered its target field and had begun synapse formation.
Rentschler et al. (2002) showed that neuregulin-1, a growth and differentiation factor essential for trabeculation of the cardiac ventricle, is sufficient to induce ectopic expression of a marker of the cardiac conduction system in the mouse. This inductive effect was restricted to a window of sensitivity between 8.5 and 10.5 days postcoitum. They described the electrical activation pattern of the 9.5-days postcoitum embryonic mouse heart and showed that treatment with neuregulin-1 results in electrophysiologic changes in the activation system consistent with a recruitment of cells to the conduction system. Thus, endocardial-derived neuregulins may be the major endogenous ligands responsible for inducing murine embryonic cardiomyocytes to differentiate into cells of the conduction system.
Stefansson et al. (2002) presented results from animal studies suggesting involvement of NRG1 in susceptibility to schizophrenia. Mutant mice heterozygous for either NRG1 or its receptor, ERBB4, showed a behavioral phenotype that overlapped with mouse models of schizophrenia. Furthermore, NRG1 hypomorphs had fewer functional NMDA receptors than wildtype mice. Stefansson et al. (2002) also demonstrated that the behavioral phenotypes of the NRG1 hypomorphs were partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.
Hippenmeyer et al. (2002) found that type I and type II Nrg1, which both contain an Ig domain, were expressed preferentially by Trkc (NTRK3; 191316)-positive dorsal root ganglion (DRG) sensory neurons at a developmental stage when proprioceptive afferents first invade muscles. In contrast, type III Nrg1, which contains a cysteine-rich domain, was expressed broadly by DRG neurons and motor neurons. Hippenmeyer et al. (2002) created mice with conditional deletion of Nrg1 in embryonic DRG and motor neurons. Elimination of all Nrg1 isoforms from DRG and motor neurons impaired muscle spindle differentiation and resulted in failure of proprioceptive afferents to elaborate annulospiral terminals. Muscle spindle differentiation proceeded normally in mice that selectively lacked type III Nrg1. Hippenmeyer et al. (2002) concluded that NRG1 signaling is critical in the early induction of muscle spindle differentiation.
Duchenne muscular dystrophy (DMD; 310200) is a fatal disorder caused by absence of dystrophin (300377). Utrophin (UTRN; 128240) is a chromosome 6-encoded dystrophin-related protein that has functional motifs in common with dystrophin. The ability of utrophin to compensate for dystrophin during development and when transgenically overexpressed provided an important impetus for identifying activators of utrophin expression. The utrophin promoter A is transcriptionally regulated in part by heregulin-mediated, extracellular signal-related kinase-dependent activation of the GABP(alpha/beta) transcription factor complex (see 600610). Therefore, this pathway offers a potential mechanism to modulate utrophin expression in muscle. Krag et al. (2004) tested the ability of heregulin to improve the dystrophic phenotype in the mdx mouse model of DMD. Intraperitoneal injections of the small peptide encoding the epidermal growth factor-like region of heregulin ectodomain for 3 months in vivo resulted in upregulation of utrophin, a marked improvement in the mechanical properties of muscle as evidenced by resistance to eccentric contraction-mediated damage, and a reduction of muscle pathology. The amelioration of dystrophic phenotype by heregulin-mediated utrophin upregulation offered a pharmacologic therapeutic modality that obviates many of the toxicity and delivery issues associated with viral vector-based gene therapy for DMD.
Escher et al. (2005) demonstrated that neuromuscular junctions (NMJs) can form in the absence of the neuregulin receptors ErbB2 and ErbB4 in mouse muscle. Postsynaptic differentiation was, however, induced by agrin (103320). Escher et al. (2005) therefore concluded that neuregulin signaling to muscle is not required for NMJ formation. The effects of neuregulin signaling to muscle may be mediated indirectly through Schwann cells.
Wood et al. (2009) mapped the expression of zebrafish Disc1 (605210) and studied its role in early embryonic development using morpholino antisense methods. There was a critical requirement for Disc1 in oligodendrocyte development by promoting specification of Olig2 (606386)-positive cells in the hindbrain and other brain regions. Disruption of Nrg1 and ErbB (EGFR; 131550) signaling in zebrafish brain development yielded similar defects to those seen in Disc1-morphant embryos. Knockdown of Disc1 or Nrg1 caused near total loss of Olig2-positive cerebellar neurons, but caused no apparent loss of spinal motor neurons. Wood et al. (2009) suggested that Disc1 and Nrg1 function in common or related pathways controlling development of oligodendrocytes and neurons from Olig2-expressing precursor cells.
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