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COMMENT Neuregulin-1 alpha, the underestimated molecule: emerging new roles in normal brain function and the pathophysiology of schizophrenia? Hans-Gert Bernstein and Bernhard Bogerts
Abstract: We comment here, from a schizophrenia research perspective, on a recent paper of Ghahramani Seno et al., which clearly shows that the splice variant neuregulin-1 alpha is able to regulate multiple genes involved in phosphorylation, acetylation, and generation of splice variants. Key words: neuregulin-1 alpha, brain function, schizophrenia, gene regulation, immunocytochemistry. Résumé : Les auteurs commentent ici, a` partir d'une perspective de recherche sur la schizophrénie, un récent article de Ghahramani Seno et al., lequel montre clairement que le variant d'épissage de la neuroréguline-1 alpha est impliqué dans la régulation de nombreux gènes impliqués dans la phosphorylation, l'acétylation et la génération de variants d'épissage. [Traduit par la Rédaction] Mots-clés : neuroréguline-1 alpha, fonction cérébrale, schizophrénie, régulation génique, immunocytochimie.
Neuregulin-1 (NRG-1) is a protein that in humans is encoded by the NRG1 gene. It is known to play a pivotal role in several developmental processes and is required also later in life. NRG-1 is produced in multiple isoforms by alternative splicing and usage of distinct promoters, which allows it to perform a wide variety of functions. All NRG-1 variants contain an epidermal growth factor (EGF)-like domain, which binds and thereby activates the cognate receptors—members of the ErbB family of molecules. One of the many NRG-1 variants is NRG-1 alpha (NRG-1␣). Unlike other NRG-1 splice variants, NRG-1␣ has comparatively rarely been studied until now. Moreover, the fact that NRG-1 isoforms with -type EGFlike domains are much more potent in most assays than their ␣-type counterparts appeared to indicate a minor role for NRG-1␣ in organ and tissue functions (with the exception of mammary gland development and breast cancer; Raj et al. 2001; Falls 2003; Bernstein et al. 2006). In their very interesting recent article about the influence of NRG-1␣ on gene expression in lymphoblastoid cells (Genome, vol. 56, iss. 10), Ghahramani Seno and colleagues provide data that convincingly show that this signalling molecule is capable of doing much more than previously thought, namely regulating the expression of multiple genes that are mainly involved in phosphorylation (protein kinase signalling), acetylation, and alternative splicing. These processes play, as the authors state, “fundamental roles in proper development and function of various tissues including the central nervous system”. The latter aspect is of special relevance for all those interested in NRG-1 function in the brain. Although there is paramount evidence in favour of a central role of NRG-1 in normal brain development, adult brain function, and the pathophysiology of various brain diseases (reviewed in Deng et al. 2013), amazingly little is known about cerebral NRG-1␣. Some years ago we and others have demonstrated that NRG-1␣ is expressed in rat, monkey, and human brain, showing a remarkable regional and cellular distribution
pattern (Bernstein et al. 2006; Connor et al. 2009). Whereas the pre- and perinatal human brain NRG-1␣ immunoreactivity was confined to numerous neurons, NRG-1␣ in the adult brain was restricted to single neurons in cortical gray and especially white matter, hypothalamus, hippocampus, basal ganglia, and brain stem. Occasionally, NRG-1␣ immunoreactive oligodendrocytes were also observed. Owing to the lack of information about possible functions of NRG-1␣ at that time, we could only speculate about the relevance of these findings. With the paper of Ghahramani Seno et al., the situation may have changed. The question, however, is what can NRG-1␣ induced gene regulation in lymphoblastoid cells teach us about the possible role of NRG-1␣ in the brain? Quite a bit, since lymphoblastoid cells represent a very good and informative paradigm to study brain-related gene expression patterns, with a vast majority of brain-expressed proteins (including neuregulin, McBride et al. 2011) being expressed in these cells as well (as discussed in Talebizadeh et al. 2008). A particularly interesting aspect of the newly discovered broad regulatory properties of NRG-1␣ is linked with neuropsychiatric disorders (i.e., schizophrenia and depression). Ghahramani Seno et al. correctly mention that the cellular processes, which they revealed to be regulated by NRG-1␣ in lymphoblastoid cell assay system, have been shown to be associated with central nervous system disorders such as schizophrenia and autism (reviewed in Engmann et al. 2011 and Ghahramani Seno et al. 2013). NRG-1 is encoded by a candidate susceptibility gene for schizophrenia (Bennett 2011 and many others). Interestingly, compared with mentally healthy controls in schizophrenia brains, the expression patterns of the NRG-1 isoforms NRG-1␣ and NRG-1 change in opposite directions. While NRG-1 mRNA and protein are significantly increased in the prefrontal cortex of schizophrenics (Hashimoto et al. 2004; Bernstein et al. 2013), the density of NRG-1␣ expressing neurons is significantly reduced in white and gray matter neurons and cerebral NRG-1␣
Received 19 September 2013. Accepted 3 October 2013. Corresponding Editor: A.K. Naumova. H.-G. Bernstein and B. Bogerts. Department of Psychiatry, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. Corresponding author: Hans-Gert Bernstein (e-mail: [email protected]). Genome 56: 703–704 (2013) dx.doi.org/10.1139/gen-2013-0171
Published at www.nrcresearchpress.com/gen on 5 November 2013.
Genome Downloaded from www.nrcresearchpress.com by Lahore University of Management Sciences (PERI) on 01/05/15 For personal use only.
704
protein levels are lower than in controls (Bertram et al. 2007; Bernstein et al. 2013). It is conceivable that decreased NRG-1␣ expression in schizophrenia reduces its regulatory influence on those genes that are active in acetylation, phosphorylation, and alternative splicing processes, which in turn may result in reduced acetylation (Engmann et al. 2011; Tang et al. 2011), phosphorylation (protein kinase signalling; Funk et al. 2012), and alternative splicing (Clinton et al. 2003) as found in schizophrenia. Thus, putting together our previous neuroanatomical findings on impaired NRG-1␣ in schizophrenia and the novel molecular biological findings of Ghahramani Seno and colleagues, NRG-1␣ seems to emerge as a new, eminent player in the game of normal and disturbed brain functioning.
References Bennett, M.R. 2011. Schizophrenia: susceptibility genes, dendritic-spine pathology and gray matter loss. Prog. Neurobiol. 95: 275–300. doi:10.1016/j. pneurobio.2011.08.003. PMID:21907759. Bernstein, H.-G., Lendeckel, U., Bertram, I., Bukowska, A., Kanakis, D., Dobrowolny, H., et al. 2006. Localization of neuregulin-1␣ (heregulin-␣) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain. Brain Res. Bull. 69(5): 546–559. doi:10.1016/j.brainresbull.2006.02.017. PMID:16647583. Bernstein, H.-G., Stricker, R., Dobrowolny, H., Steiner, J., Bogerts, B., Trübner, K., and Reiser, G. 2013. Nardilysin in human brain diseases: both friend and foe. Amino Acids, 45(2): 269–278. doi:10.1007/s00726-013-1499-8. PMID:23604405. Bertram, I., Bernstein, H.-G., Lendeckel, U., Bukowska, A., Dobrowolny, H., Keilhoff, G., et al. 2007. Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. Ann. N.Y. Acad. Sci. 1096: 147–156. doi:10.1196/annals.1397. 080. PMID:17405926. Clinton, S.M., Haroutunian, V., Davis, K.L., and Meador-Woodruff, J.H. 2003. Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am. J. Psychiatry, 160(6): 1100–1109. doi:10.1176/appi.ajp.160.6.1100. PMID:12777268.
Genome Vol. 56, 2013
Connor, C.M., Guo, Y., and Akbarian, S. 2009. Cingulate white matter neurons in schizophrenia and bipolar disorder. Biol. Psychiatry, 66(5): 486–493. doi:10. 1016/j.biopsych.2009.04.032. PMID:19559403. Deng, C., Pan, B., Engel, M., and Huang, X.-F. 2013. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway. Psychopharmacology, 226: 201– 215. doi:10.1007/s00213-013-3003-2. PMID:23389757. Engmann, O., Hortobágyi, T., Pidsley, R., Troakes, C., Bernstein, H.-G., Kreutz, M.R., et al. 2011. Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain, 134(8): 2408–2421. doi:10.1093/brain/awr155. Falls, D.L. 2003. Neuregulins: functions, forms, and signaling strategies. Exp. Cell Res. 284(1): 14–30. doi:10.1016/S0014-4827(02)00102-7. PMID:12648463. Funk, A.J., McCullumsmith, R.E., Haroutunian, V., and Meador-Woodruff, J.H. 2012. Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. Neuropsychopharmacology, 37(4): 896–905. doi:10.1038/npp.2011.267. PMID: 22048463. Ghahramani Seno, M.M., Gwadry, F.G., Hu, P., and Scherer, S.W. 2013. Neuregulin 1-alpha regulates phosphorylation, acetylation, and alternative splicing in lymphoblastoid cells. Genome, 56(10). doi:10.1139/gen-2013-0068. Hashimoto, R., Straub, R.E., Weickert, C.S., Hyde, T.M., Kleinman, J.E., and Weinberger, D.R. 2004. Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol. Psychiatry, 9: 299–307. doi:10. 1038/sj.mp.4001434. PMID:14569272. McBride, K.L., Zender, G.A., Fitzgerald-Butt, S.M., Seagraves, N.J., Fernbach, S.D., Zapata, G., et al. 2011. Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. Birth Defects Res. Part A Clin. Mol. Teratol. 91: 162–168. doi:10.1002/bdra.20764. PMID:21290564. Raj, E.H., Skinner, A., Mahji, U., Nirmala, K.N., Ravichandran, K., Shanta, V., et al. 2001. Neuregulin 1-alpha expression in locally advanced breast cancer. Breast, 10(1): 41–45. doi:10.1054/brst.2000.0182. PMID:14965558. Talebizadeh, Z., Butler, M.G., and Theodoro, M.F. 2008. Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res. 1: 240–250. doi:10.1002/aur.33. PMID:19360674. Tang, B., Dean, B., and Thomas, E.A. 2011. Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. Transl. Psychiatry, 1: e64. doi:10.1038/tp.2011.61.
Published by NRC Research Press
Genome Downloaded from www.nrcresearchpress.com by Lahore University of Management Sciences (PERI) on 01/05/15 For personal use only.
COMMENT Neuregulin-1 alpha, the underestimated molecule: emerging new roles in normal brain function and the pathophysiology of schizophrenia? Hans-Gert Bernstein and Bernhard Bogerts
Abstract: We comment here, from a schizophrenia research perspective, on a recent paper of Ghahramani Seno et al., which clearly shows that the splice variant neuregulin-1 alpha is able to regulate multiple genes involved in phosphorylation, acetylation, and generation of splice variants. Key words: neuregulin-1 alpha, brain function, schizophrenia, gene regulation, immunocytochemistry. Résumé : Les auteurs commentent ici, a` partir d'une perspective de recherche sur la schizophrénie, un récent article de Ghahramani Seno et al., lequel montre clairement que le variant d'épissage de la neuroréguline-1 alpha est impliqué dans la régulation de nombreux gènes impliqués dans la phosphorylation, l'acétylation et la génération de variants d'épissage. [Traduit par la Rédaction] Mots-clés : neuroréguline-1 alpha, fonction cérébrale, schizophrénie, régulation génique, immunocytochimie.
Neuregulin-1 (NRG-1) is a protein that in humans is encoded by the NRG1 gene. It is known to play a pivotal role in several developmental processes and is required also later in life. NRG-1 is produced in multiple isoforms by alternative splicing and usage of distinct promoters, which allows it to perform a wide variety of functions. All NRG-1 variants contain an epidermal growth factor (EGF)-like domain, which binds and thereby activates the cognate receptors—members of the ErbB family of molecules. One of the many NRG-1 variants is NRG-1 alpha (NRG-1␣). Unlike other NRG-1 splice variants, NRG-1␣ has comparatively rarely been studied until now. Moreover, the fact that NRG-1 isoforms with -type EGFlike domains are much more potent in most assays than their ␣-type counterparts appeared to indicate a minor role for NRG-1␣ in organ and tissue functions (with the exception of mammary gland development and breast cancer; Raj et al. 2001; Falls 2003; Bernstein et al. 2006). In their very interesting recent article about the influence of NRG-1␣ on gene expression in lymphoblastoid cells (Genome, vol. 56, iss. 10), Ghahramani Seno and colleagues provide data that convincingly show that this signalling molecule is capable of doing much more than previously thought, namely regulating the expression of multiple genes that are mainly involved in phosphorylation (protein kinase signalling), acetylation, and alternative splicing. These processes play, as the authors state, “fundamental roles in proper development and function of various tissues including the central nervous system”. The latter aspect is of special relevance for all those interested in NRG-1 function in the brain. Although there is paramount evidence in favour of a central role of NRG-1 in normal brain development, adult brain function, and the pathophysiology of various brain diseases (reviewed in Deng et al. 2013), amazingly little is known about cerebral NRG-1␣. Some years ago we and others have demonstrated that NRG-1␣ is expressed in rat, monkey, and human brain, showing a remarkable regional and cellular distribution
pattern (Bernstein et al. 2006; Connor et al. 2009). Whereas the pre- and perinatal human brain NRG-1␣ immunoreactivity was confined to numerous neurons, NRG-1␣ in the adult brain was restricted to single neurons in cortical gray and especially white matter, hypothalamus, hippocampus, basal ganglia, and brain stem. Occasionally, NRG-1␣ immunoreactive oligodendrocytes were also observed. Owing to the lack of information about possible functions of NRG-1␣ at that time, we could only speculate about the relevance of these findings. With the paper of Ghahramani Seno et al., the situation may have changed. The question, however, is what can NRG-1␣ induced gene regulation in lymphoblastoid cells teach us about the possible role of NRG-1␣ in the brain? Quite a bit, since lymphoblastoid cells represent a very good and informative paradigm to study brain-related gene expression patterns, with a vast majority of brain-expressed proteins (including neuregulin, McBride et al. 2011) being expressed in these cells as well (as discussed in Talebizadeh et al. 2008). A particularly interesting aspect of the newly discovered broad regulatory properties of NRG-1␣ is linked with neuropsychiatric disorders (i.e., schizophrenia and depression). Ghahramani Seno et al. correctly mention that the cellular processes, which they revealed to be regulated by NRG-1␣ in lymphoblastoid cell assay system, have been shown to be associated with central nervous system disorders such as schizophrenia and autism (reviewed in Engmann et al. 2011 and Ghahramani Seno et al. 2013). NRG-1 is encoded by a candidate susceptibility gene for schizophrenia (Bennett 2011 and many others). Interestingly, compared with mentally healthy controls in schizophrenia brains, the expression patterns of the NRG-1 isoforms NRG-1␣ and NRG-1 change in opposite directions. While NRG-1 mRNA and protein are significantly increased in the prefrontal cortex of schizophrenics (Hashimoto et al. 2004; Bernstein et al. 2013), the density of NRG-1␣ expressing neurons is significantly reduced in white and gray matter neurons and cerebral NRG-1␣
Received 19 September 2013. Accepted 3 October 2013. Corresponding Editor: A.K. Naumova. H.-G. Bernstein and B. Bogerts. Department of Psychiatry, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. Corresponding author: Hans-Gert Bernstein (e-mail: [email protected]). Genome 56: 703–704 (2013) dx.doi.org/10.1139/gen-2013-0171
Published at www.nrcresearchpress.com/gen on 5 November 2013.
Genome Downloaded from www.nrcresearchpress.com by Lahore University of Management Sciences (PERI) on 01/05/15 For personal use only.
704
protein levels are lower than in controls (Bertram et al. 2007; Bernstein et al. 2013). It is conceivable that decreased NRG-1␣ expression in schizophrenia reduces its regulatory influence on those genes that are active in acetylation, phosphorylation, and alternative splicing processes, which in turn may result in reduced acetylation (Engmann et al. 2011; Tang et al. 2011), phosphorylation (protein kinase signalling; Funk et al. 2012), and alternative splicing (Clinton et al. 2003) as found in schizophrenia. Thus, putting together our previous neuroanatomical findings on impaired NRG-1␣ in schizophrenia and the novel molecular biological findings of Ghahramani Seno and colleagues, NRG-1␣ seems to emerge as a new, eminent player in the game of normal and disturbed brain functioning.
References Bennett, M.R. 2011. Schizophrenia: susceptibility genes, dendritic-spine pathology and gray matter loss. Prog. Neurobiol. 95: 275–300. doi:10.1016/j. pneurobio.2011.08.003. PMID:21907759. Bernstein, H.-G., Lendeckel, U., Bertram, I., Bukowska, A., Kanakis, D., Dobrowolny, H., et al. 2006. Localization of neuregulin-1␣ (heregulin-␣) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain. Brain Res. Bull. 69(5): 546–559. doi:10.1016/j.brainresbull.2006.02.017. PMID:16647583. Bernstein, H.-G., Stricker, R., Dobrowolny, H., Steiner, J., Bogerts, B., Trübner, K., and Reiser, G. 2013. Nardilysin in human brain diseases: both friend and foe. Amino Acids, 45(2): 269–278. doi:10.1007/s00726-013-1499-8. PMID:23604405. Bertram, I., Bernstein, H.-G., Lendeckel, U., Bukowska, A., Dobrowolny, H., Keilhoff, G., et al. 2007. Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. Ann. N.Y. Acad. Sci. 1096: 147–156. doi:10.1196/annals.1397. 080. PMID:17405926. Clinton, S.M., Haroutunian, V., Davis, K.L., and Meador-Woodruff, J.H. 2003. Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia. Am. J. Psychiatry, 160(6): 1100–1109. doi:10.1176/appi.ajp.160.6.1100. PMID:12777268.
Genome Vol. 56, 2013
Connor, C.M., Guo, Y., and Akbarian, S. 2009. Cingulate white matter neurons in schizophrenia and bipolar disorder. Biol. Psychiatry, 66(5): 486–493. doi:10. 1016/j.biopsych.2009.04.032. PMID:19559403. Deng, C., Pan, B., Engel, M., and Huang, X.-F. 2013. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway. Psychopharmacology, 226: 201– 215. doi:10.1007/s00213-013-3003-2. PMID:23389757. Engmann, O., Hortobágyi, T., Pidsley, R., Troakes, C., Bernstein, H.-G., Kreutz, M.R., et al. 2011. Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain, 134(8): 2408–2421. doi:10.1093/brain/awr155. Falls, D.L. 2003. Neuregulins: functions, forms, and signaling strategies. Exp. Cell Res. 284(1): 14–30. doi:10.1016/S0014-4827(02)00102-7. PMID:12648463. Funk, A.J., McCullumsmith, R.E., Haroutunian, V., and Meador-Woodruff, J.H. 2012. Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. Neuropsychopharmacology, 37(4): 896–905. doi:10.1038/npp.2011.267. PMID: 22048463. Ghahramani Seno, M.M., Gwadry, F.G., Hu, P., and Scherer, S.W. 2013. Neuregulin 1-alpha regulates phosphorylation, acetylation, and alternative splicing in lymphoblastoid cells. Genome, 56(10). doi:10.1139/gen-2013-0068. Hashimoto, R., Straub, R.E., Weickert, C.S., Hyde, T.M., Kleinman, J.E., and Weinberger, D.R. 2004. Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol. Psychiatry, 9: 299–307. doi:10. 1038/sj.mp.4001434. PMID:14569272. McBride, K.L., Zender, G.A., Fitzgerald-Butt, S.M., Seagraves, N.J., Fernbach, S.D., Zapata, G., et al. 2011. Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. Birth Defects Res. Part A Clin. Mol. Teratol. 91: 162–168. doi:10.1002/bdra.20764. PMID:21290564. Raj, E.H., Skinner, A., Mahji, U., Nirmala, K.N., Ravichandran, K., Shanta, V., et al. 2001. Neuregulin 1-alpha expression in locally advanced breast cancer. Breast, 10(1): 41–45. doi:10.1054/brst.2000.0182. PMID:14965558. Talebizadeh, Z., Butler, M.G., and Theodoro, M.F. 2008. Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res. 1: 240–250. doi:10.1002/aur.33. PMID:19360674. Tang, B., Dean, B., and Thomas, E.A. 2011. Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. Transl. Psychiatry, 1: e64. doi:10.1038/tp.2011.61.
Published by NRC Research Press
