Neuregulin 3 Explained

Neuregulin 3, also known as NRG3, is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene.^{[1] [2]} The NRGs are a group of signaling proteins part of the superfamily of epidermal growth factor, EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.^[3]

The neuregulins are a diverse family of proteins formed through alternative splicing from a single gene; they play crucial roles in regulating the growth and differentiation of epithelial, glial and muscle cells. These groups of proteins also aid cell-cell associations in the breast, heart and skeletal muscles.^[4] Four different kinds of neuregulin genes have been identified, namely: NRG1 NRG2 NRG3 and NRG4. While the NRG1 isoforms have been extensively studied, there is little information available about the other genes of the family. NRGs bind to the ERBB3 and ERBB4 tyrosine kinase receptors; they then form homodimers or heterodimers, often consisting of ERBB2, which is thought to function as a co-receptor as it has not been observed to bind any ligand.^{[5] [6]} NRGs bind to the ERBB receptors to promote phosphorylation of specific tyrosine residues on the C-terminal link of the receptor and the interactions of intracellular signaling proteins.^[7]

NRGs also play significant roles in developing, maintaining, and repair of the nervous system; this is because NRG1, NRG2 and NRG3 are widely expressed in the central nervous system and also in the olfactory system. Studies have observed that in mice, NRG3 is limited to the developing Central nervous system as well as the adult form; previous studies also highlight the roles of NRG1, ERBB2, and ERBB4 in the development of the heart. Mice deficient in ERBB2, ERBB4, or NRG1 were observed to die at the mid-embryogenesis stage from the termination of myocardial trabeculae development in the ventricle. These results confirm that NRG1 expression in the endocardium is a significant ligand required to activate expression of ERBB2 and ERBB4 in the myocardium.

Function

Neuregulins are ligands of the ERBB-family receptors, while NRG1 and NRG2 are able to bind and activate both ERBB3 and ERBB4, NRG3 binding stimulates tyrosine phosphorylation, and can only bind to the extracellular domain of the ERBB4 receptor tyrosine kinase but not to the other members of the ERBB family receptors; ERBB2 and ERBB3.

NRG1, plays critical roles in the development of the embryonic cerebral cortex when it controls migration and sequencing of the cortical cell.^[8] Contrary to NRG1, there is limited information on pre-mRNA splicing of the NRG3 gene, together with its transcriptional profile and function in the brain. The recent discovery of hFBNRG3 (human fetal brain NRG3; DQ857894) which is an alternative cloned isoform of NRG3 from human fetal brain, promotes the survival of oligodendrocyte with the aid of ERBB4/PI3K/AKT1 pathway^[9] and also partakes in NRG3-ERBB4 signaling in neurodevelopment and brain functionalities.^[10]

Even though studies have revealed that NRG1 and NRG3 are paralogues, the EGF domain of NRG3 is only 31% identical to NRG1. The N-terminal domain of NRG3 resembles that of Sensory And Motor Neuron Derived Factor; SMDF^[11] because it lacks Ig-like as well as Kringle-like domains that are attributed to many NRG1 isomers. Hydropathy profile studies have shown that NRG3 lacks a hydrophobic N-terminal signal sequence common in secreted proteins, but contains a region of non-polar or uncharged amino acids in position (W66–V91). An amino acid region found in SMDF is similar to this non polar site of NRG3 and has been proposed to act as an internal, uncleaved signal sequence that functions as a translocation agent across the endoplasmic reticulum membrane.

Clinical significance

Recent human genetic studies reveals neuregulin 3 gene (NRG3) as a potential risk gene responsible for different kinds of neuro-developmental disorders, resulting to schizophrenia, stunted development, attention deficit related disorders and bipolar disorders when structural and genetic variations occur within the gene^[12]

Most importantly, variants of the NRG3 gene have been linked to a susceptibility to schizophrenia.^[13] An increase in Isoform-specific models of NRG3 involved in schizophrenia have been reported, and observed to have an interaction with rs10748842; a NRG3 risk polymorphism, which indicates that NRG3 transcriptional dysregulation is a molecular risk mechanism.^[14]

These isoforms have also been linked to Hirschsprung's disease.^[15]

Schizophrenia

Several genes in the NRG-ERBB signaling pathway have been implicated in genetic predisposition to schizophrenia, Neuregulin 3 (NRG3) encodes a protein similar to its paralog NRG1 and both play important roles in the developing nervous system. As observed with other pathologies like autism and schizophrenia, several members of any given protein family have a high chance of association with the same phenotype, individually or together.^{[16] [17]}

A recent study of the temporal, diagnostic, and tissue-specific modulation of NRG3 isoform expression in human brain development, employed the use of qRT-PCR ; quantitative polymerase chain reaction to quantify 4 classes of NRG3 in human postmortem dorsolateral prefrontal cortex from 286 normal and affected (bipolar or extreme depressive disorder) candidates with age range of 14 weeks to 85 years old. The researches observed that each the 4 isoform class (I-IV) of NRG3 showed unique expression trajectories across human neopallium development and aging.

• NRG3 class I was increased in bipolar and major depressive disorder, in agreement with observations in schizophrenia.
• NRG3 class II was increased in bipolar disorder, and class III was increased in major depression cases.
• NRG3 class I, II and IV were actively involved in the developmental stages,
• 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.

Further reading

• Benzel I, Bansal A, Browning BL, Galwey NW, Maycox PR, McGinnis R, Smart D, St Clair D, Yates P, Purvis I . Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia . Behavioral and Brain Functions . 3 . 1 . 31 . June 2007 . 17598910 . 1934910 . 10.1186/1744-9081-3-31 . free .
• Iijima M, Tomita M, Morozumi S, Kawagashira Y, Nakamura T, Koike H, Katsuno M, Hattori N, Tanaka F, Yamamoto M, Sobue G . Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP . Neurology . 73 . 17 . 1348–52 . October 2009 . 19776380 . 10.1212/WNL.0b013e3181bd1139 . 207116106 .
• Shrestha S, Irvin MR, Taylor KD, Wiener HW, Pajewski NM, Haritunians T, Delaney JA, Schambelan M, Polak JF, Arnett DK, Chen YD, Grunfeld C . A genome-wide association study of carotid atherosclerosis in HIV-infected men . AIDS . 24 . 4 . 583–92 . February 2010 . 20009918 . 3072760 . 10.1097/QAD.0b013e3283353c9e .
• Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE, David SP, Niaura R, Lerman C . Molecular genetics of successful smoking cessation: convergent genome-wide association study results . Archives of General Psychiatry . 65 . 6 . 683–93 . June 2008 . 18519826 . 2430596 . 10.1001/archpsyc.65.6.683 .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Gizatullin RZ, Muravenko OV, Al-Amin AN, Wang F, Protopopov AI, Kashuba VI, Zelenin AV, Zabarovsky ER . Human NRG3 gene Map position 10q22-q23 . Chromosome Research . 8 . 6 . 560 . 2000 . 11032326 . 10.1023/A:1009232025144 . 33340207 .
• Panchal H, Wansbury O, Parry S, Ashworth A, Howard B . Neuregulin3 alters cell fate in the epidermis and mammary gland . BMC Developmental Biology . 7 . 105 . September 2007 . 17880691 . 2110892 . 10.1186/1471-213X-7-105 . free .
• Wang YC, Chen JY, Chen ML, Chen CH, Lai IC, Chen TT, Hong CJ, Tsai SJ, Liou YJ . Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population . Biological Psychiatry . 64 . 12 . 1093–6 . December 2008 . 18708184 . 10.1016/j.biopsych.2008.07.012 . 24914991 .
• Révillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP . ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis . Annals of Oncology . 19 . 1 . 73–80 . January 2008 . 17962208 . 10.1093/annonc/mdm431 . free .
• Carteron C, Ferrer-Montiel A, Cabedo H . Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival . Journal of Cell Science . 119 . Pt 5 . 898–909 . March 2006 . 16478787 . 10.1242/jcs.02799 . free . 10261/289020 . free .
• Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A . Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 150B . 6 . 808–16 . September 2009 . 19086053 . 10.1002/ajmg.b.30902 . 44524739 . free .
• Sonuga-Barke EJ, Lasky-Su J, Neale BM, Oades R, Chen W, Franke B, Buitelaar J, Banaschewski T, Ebstein R, Gill M, Anney R, Miranda A, Mulas F, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Thompson M, Asherson P, Faraone SV . Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 147B . 8 . 1359–68 . December 2008 . 18846501 . 10.1002/ajmg.b.30860 . 5994189 .
• Volpi S, Heaton C, Mack K, Hamilton JB, Lannan R, Wolfgang CD, Licamele L, Polymeropoulos MH, Lavedan C . Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia . Molecular Psychiatry . 14 . 11 . 1024–31 . November 2009 . 18521091 . 10.1038/mp.2008.52 . free .

Notes and References

1. Web site: Entrez Gene: NRG3 neuregulin 3.
2. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ . Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4 . Proceedings of the National Academy of Sciences of the United States of America . 94 . 18 . 9562–7 . September 1997 . 9275162 . 23218 . 10.1073/pnas.94.18.9562 . 1997PNAS...94.9562Z . free .
3. Murphy S, Krainock R, Tham M . Neuregulin signaling via erbB receptor assemblies in the nervous system . Molecular Neurobiology . 25 . 1 . 67–77 . February 2002 . 11890458 . 10.1385/mn:25:1:067 . 2092870 .
4. Falls DL . Neuregulins: functions, forms, and signaling strategies . Experimental Cell Research . 284 . 1 . 14–30 . March 2003 . 12648463 . 10.1016/s0014-4827(02)00102-7 .
5. Olayioye MA, Neve RM, Lane HA, Hynes NE . The ErbB signaling network: receptor heterodimerization in development and cancer . The EMBO Journal . 19 . 13 . 3159–67 . July 2000 . 10880430 . 313958 . 10.1093/emboj/19.13.3159 .
6. Lefkowitz RJ . Identification of adenylate cyclase-coupled beta-adrenergic receptors with radiolabeled beta-adrenergic antagonists . Biochemical Pharmacology . 24 . 18 . 1651–8 . September 1975 . 11 . 10.1016/0006-2952(75)90001-5 .
7. Mautino B, Dalla Costa L, Gambarotta G, Perroteau I, Fasolo A, Dati C . Bioactive recombinant neuregulin-1, -2, and -3 expressed in Escherichia coli . Protein Expression and Purification . 35 . 1 . 25–31 . May 2004 . 15039062 . 10.1016/j.pep.2003.12.012 .
8. Schmid RS, McGrath B, Berechid BE, Boyles B, Marchionni M, Sestan N, Anton ES . Neuregulin 1-erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex . Proceedings of the National Academy of Sciences of the United States of America . 100 . 7 . 4251–6 . April 2003 . 12649319 . 153079 . 10.1073/pnas.0630496100 . 2003PNAS..100.4251S . free .
9. Carteron C, Ferrer-Montiel A, Cabedo H . Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival . Journal of Cell Science . 119 . Pt 5 . 898–909 . March 2006 . 16478787 . 10.1242/jcs.02799 . free . 10261/289020 . free .
10. Kao WT, Wang Y, Kleinman JE, Lipska BK, Hyde TM, Weinberger DR, Law AJ . Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain . Proceedings of the National Academy of Sciences of the United States of America . 107 . 35 . 15619–24 . August 2010 . 20713722 . 2932571 . 10.1073/pnas.1005410107 . 2010PNAS..10715619K . free .
11. Ho WH, Armanini MP, Nuijens A, Phillips HS, Osheroff PL . Sensory and motor neuron-derived factor. A novel heregulin variant highly expressed in sensory and motor neurons . The Journal of Biological Chemistry . 270 . 24 . 14523–32 . June 1995 . 7782315 . 10.1074/jbc.270.24.14523 . free .
12. Meier S, Strohmaier J, Breuer R, Mattheisen M, Degenhardt F, Mühleisen TW, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Wüst S . Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder . The International Journal of Neuropsychopharmacology . 16 . 3 . 549–56 . April 2013 . 22831755 . 10.1017/s1461145712000697 . free .
13. Chen PL, Avramopoulos D, Lasseter VK, McGrath JA, Fallin MD, Liang KY, Nestadt G, Feng N, Steel G, Cutting AS, Wolyniec P, Pulver AE, Valle D . Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia . American Journal of Human Genetics . 84 . 1 . 21–34 . January 2009 . 19118813 . 2668048 . 10.1016/j.ajhg.2008.12.005.
    • Sam Ohmer . February 25, 2009 . Schizophrenia symptom linked to gene mutation . The Johns Hopkins News-Letter .
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