Functional NRG1 receptors are heterodimers composed of ErbB2 with either an ErbB3, or ErbB4 moleculeThe neuregulin-I/ErbB signaling system in development and disease. Britsch S et al. (2007) Neuregulins (NRGs) comprise a large family of EGF-like signaling molecules involved in cell-cell communication during development and disease. The neuregulin family of ligands has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins. In contrast, the NRG1 proteins have been demonstrated to play important roles during the development of the nervous system, heart, and mammary glands. For example, NRG1 has essential functions in the development of neural crest cells and some of their major derivatives, like Schwann cells and sympathetic neurons. NRG1 controls the trabeculation of the myocardial musculature and the ductal differentiation of the mammary epithelium. Moreover, there is emerging evidence for the involvement of NRG signals in the development and function of several other organ systems, and in human disease, including breast cancer and schizophrenia. Many different isoforms of the Neuregulin-1 gene are synthesized. Such isoforms differ in their tissue-specific expression patterns and their biological activities, thereby contributing to the great diversity of the in vivo functions of NRG1. Neuregulins transmit their signals to target cells by interacting with transmembrane tyrosine kinase receptors of the ErbB family. This family includes four members, the epidermal growth factor receptor (EGF-R, ErbB1, ErbB2, ErbB3, and ErbB4). Receptor-ligand interaction induces the heterodimerization of receptor monomers, which in turn results in the activation of intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. In vivo, functional NRG1 receptors are heterodimers composed of ErbB2 with either an ErbB3, or ErbB4 molecule. The tissue-specific distribution of the different receptor types further contributes to the diversity and specificity of the biological functions of this signaling pathway. It is a typical feature of the Neuregulin-1/ErbB signaling pathway to control sequential steps during the development of a particular organ system. For example, this pathway functions in early precursor proliferation, maturation, as well as in the myelination of Schwann cells. The systematic analysis of genetic models that have been established by the help of conventional as well as conditional gene targeting strategies in mice was instrumental for the uncovering of the multitude of biological functions of this signaling system. In this review the basic biology of the Neuregulin-1/ErbB system and how it relates to the in vivo functions were discussed with special emphasis to transgenic techniques in mice.//////////////////
NCBI Summary:
The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]
General function
Ligand, Growth factor
Comment
Circulating neuregulin-1 levels in polycystic ovary syndrome. Arpacı H et al. (2019) Neuregulin-1 (NRG1) has been shown to be associated with the regulation of inflammation and ovulation. The aim of this study was to investigate the relationship between serum NRG1 levels and various clinical and metabolic parameters in women with polycystic ovary syndrome (PCOS). This case-controlled study included 38 women with PCOS and 46 age and body mass index (BMI)-matched controls without PCOS. The serum NRG1 levels of the women with PCOS were found to be significantly lower compared to the control group. The high sensitivity C-reactive protein (hs-CRP) levels of the PCOS subjects were significantly higher than in the control group. The circulating NRG1 levels were negatively correlated with a homeostasis model assessment of insulin resistance (HOMA-IR) and the hs-CRP in the PCOS group. There is no significant correlation between the circulating NRG1 levels and the serum insulin in the PCOS group. There was a trend toward high NRG1 levels in the PCOS subjects with high BMI, but the difference failed to reach a statistical significance. Decreased NRG1 levels in PCOS subjects may be associated with insulin resistance and a low-grade chronic inflammation. Impact statement What is already known on this subject? Although there have been many studies related to NRG1, we could not find any study explaining the relationship between NRG1 and PCOS. This study provides first and novel insights into the relationship between serum NRG1 levels and the insulin resistance in women with PCOS. What do the results of this study add? A decline in the NRG1 levels in PCOS may be associated with insulin resistance and a low-grade chronic inflammation. What are the implications of these findings for clinical practice and/or further research? Decreased NRG1 levels may play an important role in the reproductive and endocrine properties of PCOS. We think that NRG1 research may be contribute to the clarification of PCOS pathophysiology. Future research investigating NRG1 levels in obese and non-obese cases, as well as in ovulatory and anovulatory PCOS patients, will make a significant contribution to the resolution of the mystery under PCOS aetiology.//////////////////
Gonadotropin-dependent neuregulin-1 signaling regulates female rat ovarian granulosa cell survival. Chowdhury I et al. (2017) Mammalian ovarian follicular development and maturation of an oocyte competent to fertilize and develop into an embryo depends on tightly regulated spatiotemporally orchestrated crosstalk between cell death, survival and differentiation signals through extra- and intra-ovarian signals, as well as on a permissive ovarian follicular microenvironment. Neuregulin-1 (NRG1) is a member of the EGF-like factor family that mediates its effects by binding to the member of the ErbB family. Our experimental results suggest that gonadotropins promote differential expression of NRG1 and erbB receptors in granulosa cells (GCs), and NRG1 in theca cells during follicular development, and promote NRG1 secretions in the follicular fluid (FF) of rat ovaries. During estrous cycle of rat, NRG1 and erbB receptors are differentially expressed in GCs, and positively correlated with serum gonadotropins and steroid hormones. Moreover, in vitro experimental studies suggest that PKC inhibitor staurosporine (STS) caused the physical destruction of GCs by the activation of caspase-3. Exogenous NRG1 treatment of GCs delayed onset of STS-induced apoptosis and inhibited cleaved caspase-3 expressions. Moreover, exogenous NRG1 treatment of GCs alters STS-induced death through maintaining the expression of ErbB2, ErbB3, pAkt, Bcl2 and BclxL proteins. Taken together, these studies demonstrate that NRG1 is gonadotropin-dependent differentially regulated in GCs and theca cells, and secreted in ovarian FF as an intracellular survival factor that may govern follicular maturation.//////////////////
LH-Induced Neuregulin 1 (NRG1) Type III Transcripts Control Granulosa Cell Differentiation and Oocyte Maturation. Noma N et al. Epidermal growth factor (EGF)-like factors [amphiregulin (AREG), betacellulin, and epiregulin] are induced by LH and activate the EGF receptor (ERBB1)/ERK1/2 pathway in granulosa cells and cumulus cells of preovulatory follicles to impact ovulation. However, the expression and roles of other ERBB family members and their ligands have not been explored in detail. Herein, we document that two transcripts of the neuregulin (Nrg1) gene are expressed in granulosa cells, and that the type III Nrg1 is induced during ovulation in an ERK1/2 and C/EBP?dependent manner. Western blotting shows that intact (75 kDa) and secreted (45 kDa) forms of neuregulin 1 (NRG1) are present in the ovary. NRG1 likely binds to ERBB3/ERBB2 complexes that are expressed in granulosa cells and cumulus cells. In cultured granulosa cells, NRG1 selectively stimulates the phosphorylation of AKT/PKB compared to ERK1/2. However, when granulosa cells were cultured with NRG1 and AREG, the phosphorylation of ERK1/2 was markedly enhanced as compared with that by AREG alone. Cotreatment with NRG1 and AREG also increased progesterone production. When cumulus-oocyte complexes (COCs) were cultured with both NRG1 and AREG, the matured oocytes exhibited significantly higher developmental competence as compared with that of oocytes cultured with AREG alone. Collectively, these results document that the expression of type III NRG1 is induced in granulosa cells during ovulation and that NRG1 enhances AREG-induced ERK1/2 phosphorylation in both granulosa cells and cumulus cells. The NRG1 pathway has two roles: one is to enhance AREG-induced progesterone production in granulosa cells, and the other is to regulate oocyte maturation by a cumulus cell-dependent mechanism.
Expression regulated by
LH
Comment
Ovarian localization
Granulosa, Theca, Follicular Fluid
Comment
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: mouse
Mutation name: None
type: None fertility: subfertile Comment: Targeted disruption of Nrg1 in granulosa cells alters the temporal progression of oocyte maturation. Kawashima I 2014 et al.
Neuregulin 1 (NRG1) is induced in granulosa cells by LH and acts on granulosa and cumulus cells during ovulation. In this study, we sought to determine the role of NRG1 in oocyte maturation by generating a granulosa cell specific Nrg1 knockout mouse (Nrg1(flox/flox); Cyp19a1Cre mice; gcNrg1KO). In the gcNrg1KO mice, meiosis was induced 2-h earlier than in control mice. More than 60% of the oocytes in the mutant mice spontaneously re-resumed meiosis beyond the MII stage. The percentage of successful fertilization was comparable in oocytes of both genotypes collected at 14 or 16 h after hCG injection, but was significantly lower in oocytes of the gcNrg1KO mice at 18 or 20 h. The number of pups per litter was significantly decreased in gcNrg1KO mice. To determine the molecular events associated with the abnormal progression of meiosis in the gcNrg1KO mouse oocytes, the defects of cumulus/granulosa cell functions were analyzed. The expression of genes involved in luteinization and cumulus expansion was significantly higher at 2 h after hCG in the gcNrg1KO mice; this was related to abnormal activation of PKC and phosphorylation of connexin-43 in cumulus cells. Changes in connexin-43 by PKC might lead to early meiotic resumption of oocytes in gcNrg1KO mice. We conclude that NRG1 is induced by LH in mural granulosa cells and exerts an important regulatory role on oocyte meiotic maturation and competence by reducing PKC activation in cumulus cells and preventing premature progression to the MII stage that leads to abnormal fertilization and fertility.
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Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: The acceleration of reproductive aging in Nrg1(flox/flox) ;Cyp19-Cre female mice. Umehara T et al. (2017) Irregular menstrual cycles, reduced responses to exogenous hormonal treatments, and altered endocrine profiles (high FSH/high LH/low AMH) are observed in women with increasing age before menopause. In this study, because the granulosa cell-specific Nrg1 knockout mice (gcNrg1KO) presented ovarian and endocrine phenotypes similar to older women, we sought to understand the mechanisms of ovarian aging and to develop a new strategy for improving fertility in older women prior to menopause. In the ovary of 6-month-old gcNrg1KO mice, follicular development was blocked in bilayer secondary follicles and heterogeneous cells accumulated in ovarian stroma. The heterogeneous cells in ovarian stroma were distinguished as two different types: (i) the LH receptor-positive endocrine cells and (ii) actin-rich fibrotic cells expressing collagen. Both the endocrine and fibrotic cells disappeared following long-term treatment with a GnRH antagonist, indicating that the high levels of serum LH induced the survival of both cell types and the abnormal endocrine profile to reduce fertility. Moreover, follicular development to the antral stages was observed with reduced LH and the disappearance of the abnormal stromal cells. Mice treated with the GnRH antagonist regained normal, recurrent estrous cycles and continuously delivered pups for at least for 3 months. We conclude that endocrine and matrix alternations occur within the ovarian stroma with increasing age and that abolishing these alternations resets the cyclical release of LH. Thus, GnRH antagonist treatments might provide a new, noninvasive strategy for improving fertility in a subset of aging women before menopause.//////////////////
Species: human
Mutation name: type: naturally occurring fertility: fertile Comment: Out of 137,646 individuals with ultrasound scans, 476 had more than one fetus (e.g., twins). The lead associated SNP for this trait was located in the gene NRG1.
Genomic Analyses from Non-invasive Prenatal Testing Reveal Genetic Associations, Patterns of Viral Infections, and Chinese Population History. Liu S et al. (2018) We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.//////////////////