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Neuregulin: An activity-dependent synaptic modulator at the neuromuscular junction

  • Published:
Journal of Neurocytology

Abstract

Synaptic activity in the form of neurotransmitter release and postsynaptic depolarization is a prime motive force that guides synaptic development throughout the nervous system. The molecular basis of how synaptic activity is converted into structural changes that build and maintain synapses is a key question that has recently become focused on regulatory factors that act on tyrosine kinase receptors on both sides of the synaptic interface. The neuregulins are such a family of growth and differentiation factors that exist as both membrane-bound and soluble forms through alternatively splicing. Neuregulin functions to promote the local expression of acetylcholine receptors at neuromuscular synapses and therefore has the potential to strengthen specific synaptic connections. Recent evidence suggests that synaptic activity at the neuromuscular junction is coupled to presynaptic neuregulin release through an indirect mechanism acting through the postsynaptic expression of neurotrophic factors. At early stages of development, this could potentiate the stability of more active synapses. Later in development, heparin-binding forms of neuregulin accumulate to high levels in the synaptic basal lamina through the developmentally programmed expression of heparan sulfate proteoglycans, thus providing a sustained source of neuregulin to the most active synapses.

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References

  • ALCANTARA, S., FRISEN, J., DEL RIO, J. A., SORIANO, E., BARBACID, M. & SILOS-SANTIAGO, I. (1997) TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J. Neurosci. 17, 362–3633.

    PubMed  Google Scholar 

  • ALTIOK, N., ALTIOK, S. & CHANGEUX, J. P. (1997) Heregulin-stimulated acetylcholine receptor gene expression in muscle: Requirement for MAP kinase and evidence for a parallel inhibitory pathway independent of electrical activity. EMBO Journal 16, 71–725.

    PubMed  Google Scholar 

  • ALTIOK, N., BESSEREAU, J. L. & CHANGEUX, J. P. (1995) ErbB3 and ErbB2/neu mediate the effect of heregulin on acetylcholine receptor gene expression in muscle: Differential expression at the endplate. EMBO Journal 14, 425–4266.

    PubMed  Google Scholar 

  • ANDRECHEK, E. R., HARDY, W. R., GIRGISGABARDO, A. A., PERRY, R. L., BUTLER, R., GRAHAM, F. L., KAHN, R. C., RUDNICKI, M. A. & MULLER, W. J. (2002) ErbB2 is required for muscle spindle and myoblast cell survival. Mol. Cell Biol. 22, 471–4722.

    PubMed  Google Scholar 

  • BRANDON, E. P., LIN, W., D'AMOUR, K. A., PIZZO, D. P., DOMINGUEZ, B., SUGIURA, Y., THODE, S., KO, C. P., THAL, L. J., GAGE, F. H. & LEE, K. F. (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. J. Neurosci. 23, 53–549.

    PubMed  Google Scholar 

  • BRIGUET, A. & RUEGG, M. A. (2000) The Ets transcription factor GABP is required for postsynaptic differentiation in vivo. J. Neurosci. 20, 598–5996.

    PubMed  Google Scholar 

  • BRITSCH, S., LI, L., KIRCHHOFF, S., THEURING, F., BRINKMANN, V., BIRCHMEIER, C. & RIETHMACHER, D. (1998) The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. Genes Dev.,12 182–1836.

    PubMed  Google Scholar 

  • BUC-CARON, M. H., NYSTROM, P. & FISCHBACH, G. D. (1983) Induction of acetylcholine receptor synthesis and aggregation: Partial purification of low-molecular weight activity. Dev. Biol. 95, 37–386.

    PubMed  Google Scholar 

  • BUONANNO, A. & FISCHBACH, G. D. (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 28–296.

    PubMed  Google Scholar 

  • BURDEN, S. (1977) Development of the neuromuscular junction in the chick embryo: The number, distribution, and stability of acetylcholine receptors. Dev. Biol. 57, 31– 329.

    PubMed  Google Scholar 

  • BURGESS, T. L., ROSS, S. L., QIAN, Y. X., BRANKOW, D. & HU, S. (1995) Biosynthetic processing of neu differentiation factor. Glycosylation trafficking, and regulated cleavage from the cell surface. J. Biol. Chem. 270, 1918–19196.

    PubMed  Google Scholar 

  • BUSFIELD, S. J., MICHNICK, D. A., CHICKERING, T. W., REVETT, T. L., MA, J., WOOLF, E. A., COMRACK, C. A., DUSSAULT, B. J., WOOLF, J., GOODEARL, A. D. & GEARING, D. P. (1997) Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Mol. Cell Biol. 17, 400–4014.

    PubMed  Google Scholar 

  • CABEDO, H., LUNA, C., FERNANDEZ, A. M., GALLAR, J. & FERRER-MONTIEL, A. (2002) Molecular determinants of the sensory and motor neuron-derived factor insertion into plasma membrane. J. Biol. Chem. 277, 1990–19912.

    PubMed  Google Scholar 

  • CANNELLA, B., HOBAN, C. J., GAO, Y. L., GARCIA-ARENAS, R., LAWSON, D., MARCHIONNI, M., GWYNNE, D. & RAINE, C. S. (1998) The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. Proc. Natl. Acad. Sci. USA 95, 1010–10105.

    PubMed  Google Scholar 

  • CANNELLA, B., PITT, D., MARCHIONNI, M. & RAINE, C. S. (1999) Neuregulin and erbB receptor expression in normal and diseased human white matter. J. Neuroimmunol. 100, 23–242.

    PubMed  Google Scholar 

  • CARRAWAY, K. L., 3RD, WEBER, J. L., UNGER, M. J., LEDESMA, J., YU, N., GASSMANN, M. & LAI, C. (1997) Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 387, 51–516.

    PubMed  Google Scholar 

  • CHANG, C. C., CHUANG, S. T. & HUANG, M. C. (1975) Effects of chronic treatment with various neuromuscular blocking agents on the number and distribution of acetylcholine receptors in the rat diaphragm. J. Physiol. (Lond.) 250, 16–173.

    Google Scholar 

  • CHANG, H., RIESE, D. J., 2ND, GILBERT, W., STERN, D. F. & MCMAHAN, U. J. (1997) Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Nature 387, 50–512.

    PubMed  Google Scholar 

  • COHEN-CORY, S. (2002) The developing synapse: Construction and modulation of synaptic structures and circuits. Science 298, 77–776.

    PubMed  Google Scholar 

  • CORFAS, G., FALLS, D. L. & FISCHBACH, G. D. (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis, also induces tyrosine phosphorylation of a 185-kDa muscle transmembrane protein. Proceedings of the National Academy of Sciences of the United States of America 90, 162–1628.

    PubMed  Google Scholar 

  • DECHIARA, T. M., BOWEN, D. C., VALENZUELA, D. M., SIMMONS, M. V., POUEYMIROU, W. T., THOMAS, S., KINETZ, E., COMPTON, D. L., ROJAS, E., PARK, J. S., SMITH, C., DISTEFANO, P. S., GLASS, D. J., BURDEN, S. J. & YANCOPOULOS, G. D. (1996) The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85, 50–512.

    PubMed  Google Scholar 

  • DIAZ-RODRIGUEZ, E., ESPARIS-OGANDO, A., MONTERO, J. C., YUSTE, L. & PANDIELLA, A. (2000) Stimulation of cleavage of membrane proteins by calmodulin inhibitors. Biochem. J. 346(Pt 2), 35–367.

    PubMed  Google Scholar 

  • EILAM, R., PINKAS-KRAMARSKI, R., RATZKIN, B. J., SEGAL, M. & YARDEN, Y. (1998) Activity-dependent regulation of Neu differentiation factor/neuregulin expression in rat brain. Proc. Natl. Acad. Sci. USA 95, 188–1893.

    PubMed  Google Scholar 

  • ERICKSON, S. L., O'SHEA, K. S., GHABOOSI, N., LOVERRO, L., FRANTZ, G., BAUER, M., LU, L. H. & MOORE, M. W. (1997) ErbB3 is required for normal cerebellar and cardiac development: A comparison with ErbB2-and heregulin-deficient mice. Development 124, 499–5011.

    PubMed  Google Scholar 

  • ERNFORS, P. (2001) Local and target-derived actions of neurotrophins during peripheral nervous system development. Cell Mol. Life Sci. 58, 103–1044.

    PubMed  Google Scholar 

  • FALLON, J. R. & GELFMAN, C. E. (1989) Agrin-related molecules are concentrated at acetylcholine receptor clusters in normal and aneural developing muscle. J. Cell Biol. 108, 152–1535.

    PubMed  Google Scholar 

  • FALLS, D. L., ROSEN, K. M., CORFAS, G., LANE, W. S. & FISCHBACH, G. D. (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72, 80–815.

    PubMed  Google Scholar 

  • FERTUCK, H. C. & SALPETER, M. M. (1976) Quantitation of junctional and extrajunctional acetylcholine receptors by electron microscope autoradiography after 125I-alpha-bungarotoxin binding at mouse neuromuscular junctions. J. Cell Biol. 69, 14–158.

    PubMed  Google Scholar 

  • FISCHBACH, G. D. & COHEN, S. A. (1973) The distribution of acetylcholine sensitivity over uninnervated and innervated muscle fibers grown in cell culture. Dev. Biol. 31, 14–162.

    PubMed  Google Scholar 

  • FISCHBACH, G. D. & ROSEN, K. M. (1997) ARIA: A neuromuscular junction neuregulin. Annual Review of Neuroscience 20, 42–458.

    PubMed  Google Scholar 

  • FROMM, L. & BURDEN, S. J. (1998) Synapse-specific and neuregulin-induced transcription require an ets site that binds GABPalpha/GABPbeta. Genes Dev. 12, 307–3083.

    PubMed  Google Scholar 

  • FROMM, L. & BURDEN, S. J. (2001) Neuregulin-1-stimulated phosphorylation of GABP in skeletal muscle cells. Biochemistry 40, 530–5312.

    PubMed  Google Scholar 

  • FUNAKOSHI, H., BELLUARDO, N., ARENAS, E., YAMAMOTO, Y., CASABONA, A., PERSSON, H. & IBANEZ, C. F. (1995) Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science 268, 149–1499.

    PubMed  Google Scholar 

  • GARCES, A., HAASE, G., AIRAKSINEN, M. S., LIVET, J., FILIPPI, P. & DELAPEYRIERE, O. (2000) GFRalpha 1 is required for development of distinct subpopulations of motoneuron. J. Neurosci. 20, 499–5000.

    PubMed  Google Scholar 

  • GASSMANN, M., CASAGRANDA, F., ORIOLI, D., SIMON, H., LAI, C., KLEIN, R. & LEMKE, G. (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 39–394.

    PubMed  Google Scholar 

  • GASSMANN, M. & LEMKE, G. (1997) Neuregulins and neuregulin receptors in neural development. Curr. Opin. Neurobiol. 7, 8–92.

    PubMed  Google Scholar 

  • GAUTAM, M., NOAKES, P. G., MOSCOSO, L., RUPP, F., SCHELLER, R. H., MERLIE, J. P. & SANES, J. R. (1996) Defective neuromuscular synaptogenesis in agrindeficient mutant mice. Cell 85, 52–535.

    PubMed  Google Scholar 

  • GONZALEZ, M., RUGGIERO, F. P., CHANG, Q., SHI, Y. J., RICH, M. M., KRANER, S. & BALICE-GORDON, R. J. (1999) Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions. Neuron 24, 56–583.

    PubMed  Google Scholar 

  • GOODEARL, A. D., YEE, A. G., SANDROCK, A. W., JR., CORFAS, G. & FISCHBACH, G. D. (1995) ARIAis concentrated in the synaptic basal lamina of the developing chick neuromuscular junction. J. Cell Biol. 130, 142–1434.

    PubMed  Google Scholar 

  • HAASE, G., DESSAUD, E., GARCES, A., DE BOVIS, B., BIRLING, M., FILIPPI, P., SCHMALBRUCH, H., ARBER, S. & DELAPEYRIERE, O. (2002) GDNF acts through PEA3 to regulate cell body positioning and muscle innervation of specific motor neuron pools. Neuron 35, 89–905.

    PubMed  Google Scholar 

  • HALL, Z. W. & SANES, J. R. (1993) Synaptic structure and development: The neuromuscular junction. Cell 72(Suppl), 9–121.

    PubMed  Google Scholar 

  • HAN, B. & FISCHBACH, G. D. (1999) The release of acetylcholine receptor inducing activity (ARIA) from its transmembrane precursor in transfected fibroblasts. J. Biol. Chem. 274, 2640–26415.

    PubMed  Google Scholar 

  • HARARI, D., TZAHAR, E., ROMANO, J., SHELLY, M., PIERCE, J. H., ANDREWS, G. C. & YARDEN, Y. (1999) Neuregulin-4: A novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 18, 268–2689.

    PubMed  Google Scholar 

  • HENDERSON, C. E., CAMU, W., METTLING, C., GOUIN, A., POULSEN, K., KARIHALOO, M., RULLAMAS, J., EVANS, T., MCMAHON, S. B., ARMANINI, M. P. et al. (1993) Neurotrophins promote motor neuron survival and are present in embryonic limb bud (see comments). Nature 363, 26–270.

    PubMed  Google Scholar 

  • HENDERSON, C. E., PHILLIPS, H. S., POLLOCK, R. A., DAVIES, A. M., LEMEULLE, C., ARMANINI, M., SIMMONS, L., MOFFET, B., VANDLEN, R. A., SIMPSON, L. C. et al. (1994) GDNF: A potent survival factor for motoneurons present in peripheral nerve and muscle [see comments] [published erratum appears in Science 1995 Feb 10;267(5199):777]. Science 266, 106–1064.

    PubMed  Google Scholar 

  • HOCH, W. (1999) Formation of the neuromuscular junction. Agrin and its unusual receptors. Eur. J. Biochem. 265, –10.

    PubMed  Google Scholar 

  • HOLMES, W. E., SLIWKOWSKI, M. X., AKITA, R. W., HENZEL, W. J., LEE, J., PARK, J. W., YANSURA, D., ABADI, N., RAAB, H., LEWIS, G. D. et al (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256, 120–1210.

    PubMed  Google Scholar 

  • HORY-LEE, F. & FRANK, E. (1995) The nicotinic blocking agents d-tubocurare and alpha-bungarotoxin save motoneurons from naturally occurring death in the absence of neuromuscular blockade. J. Neurosci. 15, 645–6460.

    PubMed  Google Scholar 

  • HSUEH, Y. P. & SHENG, M. (1999) Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK/LIN-2 during rat brain development. J. Neurosci. 19, 741–7425.

    PubMed  Google Scholar 

  • ISHIGURO, H., HIGASHIYAMA, S., YAMADA, K., ICHINO, N., TANIGUCHI, N. & NAGATSU, T. (1998) [Structure and function of a novel ErbB ligand, NTAK]. Nihon Shinkei Seishin Yakurigaku Zasshi 18, 13–142.

    PubMed  Google Scholar 

  • JESSELL, T. M., SIEGEL, R. E. & FISCHBACH, G. D. (1979) Induction of acetylcholine receptors on cultured skeletal muscle by a factor extracted from brain and spinal cord. Proc. Natl. Acad. Sci. USA 76, 539–5401.

    PubMed  Google Scholar 

  • KOGAYA, Y., KIM, S., HARUNA, S. & AKISAKA, T. (1990) Heterogeneity of distribution pattern at the electron microscopic level of heparan sulfate in various basement membranes. J. Histochem. Cytochem. 38, 145–1467.

    PubMed  Google Scholar 

  • KOLIATSOS, V. E., CLATTERBUCK, R. E., WINSLOW, J. W., CAYOUETTE, M. H. & PRICE, D. L. (1993) Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron 10, 35–367.

    PubMed  Google Scholar 

  • KRAMER, R., BUCAY, N., KANE, D. J., MARTIN, L. E., TARPLEY, J. E. & THEILL, L. E. (1996) Neuregulins with an Ig-like domain are essential for mouse myocardial and neuronal development. Proc. Natl. Acad. Sci.USA 93, 483–4838.

    PubMed  Google Scholar 

  • KUFFLER, S. W. & YOSHIKAMI, D. (1975) The number of transmitter molecules in a quantum: An estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J. Physiol. 251, 46–482.

    PubMed  Google Scholar 

  • LANDER, A. D. & SELLECK, S. B. (2000) The elusive functions of proteoglycans: In vivo veritas. J. Cell Biol. 148, 22–232.

    PubMed  Google Scholar 

  • LEE, K. F., SIMON, H., CHEN, H., BATES, B., HUNG, M. C. & HAUSER, C. (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 39–398.

    PubMed  Google Scholar 

  • LI, Q. & LOEB, J. A. (2001) Neuregulin-heparan-sulfate proteoglycan interactions produce sustained erbB receptor activation required for the induction of acetylcholine receptors in muscle. J. Biol. Chem. 276, 3806–38075.

    PubMed  Google Scholar 

  • LIU, X., HWANG, H., CAO, L., BUCKLAND, M., CUNNINGHAM, A., CHEN, J., CHIEN, K. R., GRAHAM, R. M. & ZHOU, M. (1998) Domain-specific gene disruption reveals critical regulation of neuregulin signaling by its cytoplasmic tail. Proc. Natl. Acad. Sci.USA 95, 1302–13029.

    PubMed  Google Scholar 

  • LIU, Y., FORD, B., MANN, M. A. & FISCHBACH, G. D. (2001) Neuregulins increase alpha7 nicotinic acetylcholine receptors and enhance excitatory synaptic transmission in GABAergic interneurons of the hippocampus. J. Neurosci. 21, 566–5669.

    PubMed  Google Scholar 

  • LO, D. C. (1995) Neurotrophic factors and synaptic plasticity. Neuron 15, 97–981.

    PubMed  Google Scholar 

  • LOEB, J. A. & FISCHBACH, G. D. (1995) ARIA can be released from extracellular matrix through cleavage of a heparin-binding domain. Journal of Cell Biology 130, 12–135.

    PubMed  Google Scholar 

  • LOEB, J. A. & FISCHBACH, G. D. (1997) Neurotrophic factors increase neuregulin expression in embryonic ventral spinal cord neurons. Journal of Neuroscience 17, 141–1424.

    PubMed  Google Scholar 

  • LOEB, J. A., HMADCHA, A., FISCHBACH, G. D., LAND, S. J. & ZAKARIAN, V. L. (2002) Neuregulin expression at neuromuscular synapses is modulated by synaptic activity and neurotrophic factors. J. Neurosci. 22, 220–2214.

    PubMed  Google Scholar 

  • LOEB, J. A., KHURANA, T. S., ROBBINS, J. T., YEE, A. G. & FISCHBACH, G. D. (1999) Expression patterns of transmembrane and released forms of neuregulin during spinal cord and neuromuscular synapse development. Development 126, 78–791.

    PubMed  Google Scholar 

  • LOEB, J. A., SUSANTO, E. T. & FISCHBACH, G. D. (1998) The neuregulin precursor proARIA is processed to ARIA after expression on the cell surface by a protein kinase C enhanced mechanism. Molecular & Cellular Neurosciences 11, 7–91.

    Google Scholar 

  • LU, B. & FIGUROV, A. (1997) Role of neurotrophins in synapse development and plasticity. Rev. Neurosci. 8, –12.

    PubMed  Google Scholar 

  • MARCHIONNI, M. A., GOODEARL, A. D., CHEN, M. S., BERMINGHAM-MCDONOGH, O., KIRK, C., HENDRICKS, M., DANEHY, F., MISUMI, D., SUDHALTER, J., KOBAYASHI, K. et al. (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362, 31–318.

    PubMed  Google Scholar 

  • MARCHIONNI, M. A., KIRK, C. J., ISAACS, I. J., HOBAN, C. J., MAHANTHAPPA, N. K., ANTON, E. S., CHEN, C., WASON, F., LAWSON, D., HAMERS, F. P., CANOLL, P. D., REYNOLDS, R., CANNELLA, B., MEUN, D., HOLT, W. F., MATTHEW, W. D., CHEN, L. E., GISPEN, W. H., RAINE, C. S., SALZER, J. L. & GWYNNE, D. I. (1996) Neuregulins as potential drugs for neurological disorders. Cold Spring Harb. Symp. Quant. Biol. 61, 45–472.

    PubMed  Google Scholar 

  • MARTINOU, J. C., FALLS, D. L., FISCHBACH, G. D. & MERLIE, J. P. (1991) Acetylcholine receptor-inducing activity stimulates expression of the epsilon-subunit gene of the muscle acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America 88, 766–7673.

    PubMed  Google Scholar 

  • MATTHEWS-BELLINGER, J. A. & SALPETER, M. M. (1983) Fine structural distribution of acetylcholine receptors at developing mouse neuromuscular junctions. J. Neurosci. 3, 64–657.

    PubMed  Google Scholar 

  • MCALLISTER, K. A., KATZ, L. C. & LO, D. C. (1999) Neurotrophins and synaptic plasticity. Annual Review of Neuroscience 22, 29–318.

    PubMed  Google Scholar 

  • MEIER, T., MASCIULLI, F., MOORE, C., SCHOUMACHER, F., EPPENBERGER, U., DENZER, A. J., JONES, G. & BRENNER, H. R. (1998) Agrin can mediate acetylcholine receptor gene expression in muscle by aggregation of muscle-derived neuregulins. J. Cell Biol. 141, 71–726.

    PubMed  Google Scholar 

  • MEYER, D. & BIRCHMEIER, C. (1995) Multiple essential functions of neuregulin in development. Nature 378, 38–390.

    PubMed  Google Scholar 

  • MEYER, D., YAMAAI, T., GARRATT, A., RIETHMACHER-SONNENBERG, E., KANE, D., THEILL, L. E. & BIRCHMEIER, C. (1997) Isoformspecific expression and function of neuregulin. Development 124, 357–3586.

    PubMed  Google Scholar 

  • MIRSKY, R., JESSEN, K. R., BRENNAN, A., PARKINSON, D., DONG, Z., MEIER, C., PARMANTIER, E. & LAWSON, D. (2002) Schwann cells as regulators of nerve development. J. Physiol. Paris 96, 1–24.

    PubMed  Google Scholar 

  • MISGELD, T., BURGESS, R. W., LEWIS, R. M., CUNNINGHAM, J. M., LICHTMAN, J. W. & SANES, J. R. (2002) Roles of neurotransmitter in synapse formation: Development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36, 63–648.

    PubMed  Google Scholar 

  • MONTERO, J. C., YUSTE, L., DIAZ-RODRIGUEZ, E., ESPARIS-OGANDO, A. & PANDIELLA, A. (2000) Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Molecular & Cellular Neurosciences 16, 63–648.

    Google Scholar 

  • MOORE, C., LEU, M., MULLER, U. & BRENNER, H. R. (2001) Induction of multiple signaling loops by MuSK during neuromuscular synapse formation. Proc. Natl. Acad. Sci. USA 98, 1465–14660.

    PubMed  Google Scholar 

  • MOORE, M. W., KLEIN, R. D., FARINAS, I., SAUER, H., ARMANINI, M., PHILLIPS, H., REICHARDT, L. F., RYAN, A. M., CARVER-MOORE, K. & ROSENTHAL, A. (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 7–79.

    PubMed  Google Scholar 

  • MORRIS, J. K., LIN, W., HAUSER, C., MARCHUK, Y., GETMAN, D. & LEE, K. F. (1999) Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23, 27–283.

    PubMed  Google Scholar 

  • MOSCOSO, L. M., CHU, G. C., GAUTAM, M., NOAKES, P. G., MERLIE, J. P. & SANES, J. R. (1995) Synapse associated expression of an acetylcholine receptorinducing protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle. Developmental Biology 172, 15–169.

    PubMed  Google Scholar 

  • NG, Y. P., PUN, S., YANG, J. F., IP, N. Y. & TSIM, K. W. (1997) Chick muscle expresses various ARIA isoforms: Regulation during development, denervation, and regeneration. Molecular & Cellular Neurosciences 9, 13– 143.

    Google Scholar 

  • NGUYEN, Q. T., PARSADANIAN, A. S., SNIDER, W. D. & LICHTMAN, J. W. (1998) Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science 279, 172–1729.

    PubMed  Google Scholar 

  • OPPENHEIM, R. W. (1996) Neurotrophic survival molecules for motoneurons: An embarrassment of riches. Neuron 17, 19–197.

    PubMed  Google Scholar 

  • OPPENHEIM, R. W., BURSZTAJN, S. & PREVETTE, D. (1989) Cell death of motoneurons in the chick embryo spinal cord. XI. Acetylcholine receptors and synaptogenesis in skeletal muscle following the reduction of motoneuron death by neuromuscular blockade. Development 107, 33–341.

    PubMed  Google Scholar 

  • OPPENHEIM, R. W., HOUENOU, L. J., PARSADANIAN, A. S., PREVETTE, D., SNIDER, W. D. & SHEN, L. (2000) Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: Regulation of programmed cell death among motoneuron subtypes. J. Neurosci. 20, 500–5011.

    PubMed  Google Scholar 

  • OZAKI, M., SASNER, M., YANO, R., LU, H. S. & BUONANNO, A. (1997) Neuregulin-beta induces expression of an NMDA-receptor subunit. Nature 390, 69–694.

    PubMed  Google Scholar 

  • PERRIMON, N. & BERNFIELD, M. (2000) Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404, 72–728.

    PubMed  Google Scholar 

  • PESCHON, J. J., SLACK, J. L., REDDY, P., STOCKING, K. L., SUNNARBORG, S. W., LEE, D. C., RUSSELL, W. E., CASTNER, B. J., JOHNSON, R. S., FITZNER, J. N., BOYCE, R. W., NELSON, N., KOZLOSKY, C. J., WOLFSON, M. F., RAUCH, C. T., CERRETTI, D. P., PAXTON, R. J., MARCH, C. J. & BLACK, R. A. (1998) Anessential role for ectodomain shedding inmammalian development. Science 282, 128–1284.

    PubMed  Google Scholar 

  • RIEFF, H. I., RAETZMAN, L. T., SAPP, D. W., YEH, H. H., SIEGEL, R. E. & CORFAS, G. (1999) Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells. J.Neurosci. 19, 1075–10766.

    PubMed  Google Scholar 

  • RIETHMACHER, D., S ONNENBERG-RIETHMACHER, E., BRINKMANN, V., YAMAAI, T., LEWIN, G. R. & BIRCHMEIER, C. (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389, 72–730.

    PubMed  Google Scholar 

  • RIMER, M., COHEN, I., LOMO, T., BURDEN, S. J. & MCMAHAN, U. J. (1998) Neuregulins and erbB receptors at neuromuscular junctions and at agrin induced postsynaptic-like apparatus in skeletal muscle. Molecular & Cellular Neurosciences 12, –15.

    Google Scholar 

  • RUEGG, M. A. & BIXBY, J. L. (1998) Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction. Trends Neurosci. 21, 2–27.

    PubMed  Google Scholar 

  • SANCHEZ, M. P., SILOS-SANTIAGO, I., FRISEN, J., HE, B., LIRA, S. A. & BARBACID, M. (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 7–73.

    PubMed  Google Scholar 

  • SANDROCK, A. W., JR., DRYER, S. E., ROSEN, K. M., GOZANI, S. N., KRAMER, R., THEILL, L. E. & FISCHBACH, G. D. (1997) Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276, 59–603.

    PubMed  Google Scholar 

  • SANDROCK, A. W., JR., GOODEARL, A. D., YIN, Q. W., CHANG, D. & FISCHBACH, G. D. (1995) ARIA is concentrated in nerve terminals at neuromuscular junctions and at other synapses. J. Neurosci 15, 612–6136.

    PubMed  Google Scholar 

  • SANES, J. R. (1989) Extracellular matrix molecules that influence neural development. Annual Review of Neuroscience 12, 49–516.

    PubMed  Google Scholar 

  • SANES, J. R. & LICHTMAN, J. W. (1999) Development of the vertebrate neuromuscular junction. Annual Review of Neuroscience 22, 38–442.

    PubMed  Google Scholar 

  • SANES, J. R. & LICHTMAN, J. W. (2001) Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat. Rev. Neurosci. 2, 79–805.

    PubMed  Google Scholar 

  • SAPRU, M. K. (2001) Neuregulin-1 regulates expression of the Ets-2 transcription factor. Life Sci. 69, 266–2674.

    PubMed  Google Scholar 

  • SAPRU, M. K., FLORANCE, S. K., KIRK, C. & GOLDMAN, D. (1998) Identification of a neuregulin and protein-tyrosine phosphatase response element in the nicotinic acetylcholine receptor epsilon subunit gene: Regulatory role of an Rts transcription factor. Proc. Natl. Acad. Sci. USA 95, 128–1294.

    PubMed  Google Scholar 

  • SCHAEFFER, L., DE KERCHOVE D'EXAERDE, A. & CHANGEUX, J. P. (2001) Targeting transcription to the neuromuscular synapse. Neuron 31, 1–22.

    PubMed  Google Scholar 

  • SCHROERING, A. & CAREY, D. J. (1998) Sensory and motor neuron-derived factor is a transmembrane heregulin that is expressed on the plasma membrane with the active domain exposed to the extracellular environment. J. Biol. Chem. 273, 3064–30650.

    PubMed  Google Scholar 

  • SI, J., LUO, Z. & MEI, L. (1996) Induction of acetylcholine receptor gene expression by ARIA requires activation of mitogen-activated protein kinase. J. Biol. Chem. 271, 1975–19759.

    PubMed  Google Scholar 

  • SI, J., WANG, Q. & MEI, L. (1999) Essential roles of c-JUN and c-JUN N-terminal kinase (JNK) in neuregulinincreased expression of the acetylcholine receptor epsilon-subunit. J. Neurosci. 19, 849–8508.

    PubMed  Google Scholar 

  • SNIDER, W. D. (1994) Functions of the neurotrophins during nervous system development: What the knockouts are teaching us. Cell 77, 62–638.

    PubMed  Google Scholar 

  • STEFANSSON, H., SARGINSON, J., KONG, A., YATES, P., STEINTHORSDOTTIR, V., GUDFINNSSON, E., GUNNARSDOTTIR, S., WALKER, N., PETURSSON, H., CROMBIE, C., INGASON, A., GULCHER, J. R., STEFANSSON, K. & CLAIR, D. S. (2003) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am. J. Hum. Genet. 72, 8–87.

    PubMed  Google Scholar 

  • STEFANSSON, H., SIGURDSSON, E., STEINTHORSDOTTIR, V., BJORNSDOTTIR, S., SIGMUNDSSON, T., GHOSH, S., BRYNJOLFSSON, J., GUNNARSDOTTIR, S., IVARSSON, O., CHOU, T. T., HJALTASON, O., BIRGISDOTTIR, B., JONSSON, H., GUDNADOTTIR, V. G., GUDMUNDSDOTTIR, E., BJORNSSON, A., INGVARSSON, B., INGASON, A., SIGFUSSON, S., HARDARDOTTIR, H., HARVEY, R. P., LAI, D., ZHOU, M., BRUNNER, D., MUTEL, V., GONZALO, A., LEMKE, G., SAINZ, J., JOHANNESSON, G., ANDRESSON, T., GUDBJARTSSON, D., MANOLESCU, A., FRIGGE, M. L., GURNEY, M. E., KONG, A., GULCHER, J. R., PETURSSON, H. & STEFANSSON, K. (2002) Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 87–892.

    PubMed  Google Scholar 

  • STOOP, R. & POO, M. M. (1996) Synaptic modulation by neurotrophic factors. Prog. Brain Res. 109, 35– 364.

    PubMed  Google Scholar 

  • SUAREZ, E., BACH, D., CADEFAU, J., PALACIN, M., ZORZANO, A. & GUMA, A. (2001) A novel role of neuregulin in skeletal muscle. Neuregulin stimulates glucose uptake, glucose transporter translocation, and transporter expression in muscle cells. J. Biol. Chem. 276, 1825–18264.

    PubMed  Google Scholar 

  • TANOWITZ, M., SI, J., YU, D. H., FENG, G. S. & MEI, L. (1999) Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2 J.Neurosci. 19, 942–9435.

    PubMed  Google Scholar 

  • TANSEY, M. G., CHU, G. C. & MERLIE, J. P. (1996) ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway. Journal of Cell Biology 134, 46–476.

    PubMed  Google Scholar 

  • THOENEN, H. (1995) Neurotrophins and neuronal plasticity. Science 270, 59–598.

    PubMed  Google Scholar 

  • USDIN, T. B. & FISCHBACH, G. D. (1986) Purification and characterization of a polypeptide from chick brain that promotes the accumulation of acetylcholine receptors in chick myotubes. J. Cell Biol. 103, 49–507.

    PubMed  Google Scholar 

  • WANG, C. Y., YANG, F., HE, X. P., JE, H. S., ZHOU, J. Z., ECKERMANN, K., KAWAMURA, D., FENG, L., SHEN, L. & LU, B. (2002) Regulation of neuromuscular synapse development by glial cell line-derived neurotrophic factor and neurturin. J. Biol. Chem. 277, 1061–10625.

    PubMed  Google Scholar 

  • WANG, J. Y., MILLER, S. J. & FALLS, D. L. (2001) The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain. J. Biol. Chem. 276, 284–2851.

    PubMed  Google Scholar 

  • WEN, D., PELES, E., CUPPLES, R., SUGGS, S. V., BACUS, S. S., LUO, Y., TRAIL, G., HU, S., SILBIGER, S. M., LEVY, R. B. et al. (1992) Neu differentiation factor: A transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell 69, 55–572.

    PubMed  Google Scholar 

  • WEN, D., SUGGS, S. V., KARUNAGARAN, D., LIU, N., CUPPLES, R. L., LUO, Y., JANSSEN, A. M., BENBARUCH, N., TROLLINGER, D. B., JACOBSEN, V. L. et al. (1994) Structural and functional aspects of the multiplicity of Neu differentiation factors. Mol. Cell Biol. 14, 190–1919.

    PubMed  Google Scholar 

  • WOLDEYESUS, M. T., BRITSCH, S., RIETHMACHER, D., XU, L., SONNENBERG-RIETHMACHER, E., ABOU-REBYEH, F., HARVEY, R., CARONI, P. & BIRCHMEIER, C. (1999) Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development. Genes Dev. 13, 253–2548.

    PubMed  Google Scholar 

  • WOLPOWITZ, D., MASON, T. B., DIETRICH, P., MENDELSOHN, M., TALMAGE, D. A. & ROLE, L. W. (2000) Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 25, 7–91.

    PubMed  Google Scholar 

  • WON, S., SI, J., COLLEDGE, M., RAVICHANDRAN, K. S., FROEHNER, S. C. & MEI, L. (1999) Neuregulin increased expression of acetylcholine receptor epsilonsubunit gene requires ErbB interaction with Shc. J. Neurochem. 73, 235–2368.

    PubMed  Google Scholar 

  • YANG, X., KUO, Y., DEVAY, P., YU, C. & ROLE, L. (1998) A cysteine-rich isoform of neuregulin controls the level of expression of neuronal nicotinic receptor channels during synaptogenesis. Neuron 20, 25–270.

    PubMed  Google Scholar 

  • ZHU, X., LAI, C., THOMAS, S. & BURDEN, S. J. (1995) Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses. EMBO Journal 14, 584–5848.

    PubMed  Google Scholar 

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    Jeffrey A. Loeb

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Loeb, J.A. Neuregulin: An activity-dependent synaptic modulator at the neuromuscular junction. J Neurocytol 32, 649–664 (2003). https://doi.org/10.1023/B:NEUR.0000020640.84708.35

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