Interactive Fly, Drosophila

Neuregulin and neuregulin receptor mutation

Neuregulins contain an epidermal growth factor-like domain located C-terminally to either an Ig-like domain or a cysteine-rich domain specific to the sensory and motor neuron-derived isoform. Here it is shown that elimination of the Ig-like domain-containing neuregulins by homologous recombination results in embryonic lethality associated with a deficiency of ventricular myocardial trabeculation and impairment of cranial ganglion development. The erbB receptors are expressed in myocardial cells and presumably mediate the neuregulin signal originating from endocardial cells. The trigeminal ganglion is reduced in size and lacks projections toward the brain stem and mandible. It is concluded that Ig-domain-containing neuregulins play a major role in cardiac and neuronal development (Kramer, 1996).

The developmental role of erbB2 in mammals was studied in mice carrying an erbB2 null allele. Mutant embryos die before E11, probably as a result of dysfunctions associated with a lack of cardiac trabeculae. Development of cranial neural-crest-derived sensory ganglia is markedly affected. The development of motor nerves is also compromised. These results demonstrate the importance of erbB2 in neural and cardiac development (Lee, 1995).

ErbB4 neuregulin receptor is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS). Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle. They also display striking alterations in innervation of the hindbrain in the CNS, consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5. Similarities in the cardiac phenotype of ErbB4 and neuregulin gene mutants suggest that ErbB4 functions as a neuregulin receptor in the heart; however, differences in the hindbrain phenotypes of these mutants are consistent with the action of a new ErbB4 ligand in the CNS (Gassmann, 1995).

Neuregulin can bind directly to erbB3 and erbB4; receptor heterodimerization allows neuregulin-dependent activation of erbB2. A targeted mutation in mice reveals multiple essential roles of neuregulin in development. Neuregulin -/- embryos die during embryogenesis and display heart malformations. In addition, Schwann cell precursors and cranial ganglia fail to develop normally. The phenotype demonstrates that in vivo neuregulin acts locally and frequently in a paracrine manner. All cell types affected by the mutation express either erbB3 or erbB4, indicating that either of these tyrosine kinase receptors can be a component in recognition and transmission of essential neuregulin signals (Meyer, 1995).

Heregulins bind directly to ErbB3 and ErbB4 receptors, leading to multiple dimerization possibilities including heterodimerization with the ErbB2 receptor. ErbB3-, ErbB2- and heregulin-deficient mice have been generated to assess the roles of heregulins in development and differentiation. Heregulin(-/-) and ErbB2(-/-) embryos die on E10.5 due to a lack of cardiac ventricular myocyte differentiation; ErbB3(-/-) embryos survive until E13.5 exhibiting cardiac cushion abnormalities leading to blood reflux through defective valves. In ErbB3(-/-) embryos, the midbrain/hindbrain region was strikingly affected, with little differentiation of the cerebellar plate. engrailed and wnt expression are altered in the cerebellar region of ErbB3 deficient embryos. Cranial ganglia defects, while present in all three nulls, are less severe in ErbB3(-/-) embryos. The cranial ganglia defects, along with a dramatic reduction in Schwann cells, enteric ganglia and adrenal chromaffin cells, suggest a generalized effect on the neural crest. Numerous organs, including the stomach and pancreas also exhibit anomalous development (Erickson, 1997).

The different epidermal growth factor (EGF)-related peptides elicit a diverse array of biological responses as the result of their ability to activate distinct subsets of ErbB receptor dimers, leading to the recruitment of different intracellular signaling networks. To specifically examine dimerization-dependent modulation of receptor signaling, NIH 3T3 cell lines were constructed expressing ErbB-1 and ErbB-2 singly and in pairwise combinations with other ErbB family members. This model system allows the comparison of EGF-activated ErbB-1 with ErbB-1 activated by Neu differentiation factor (NDF)-induced heterodimerization with ErbB-4. In both cases, ErbB-1 couples to the adaptor protein Shc, but only when activated by EGF is it able to interact with Grb2. Compared to the rapid internalization of EGF-activated ErbB-1, NDF-activated ErbB-1 shows delayed internalization characteristics. Furthermore, the p85 subunit of phosphatidylinositol kinase (PI3-K) associates with EGF-activated ErbB-1 in a biphasic manner, whereas association with ErbB-1 transactivated by ErbB-4 is monophasic. The signaling properties of ErbB-2 following heterodimerization with the other ErbB receptors or homodimerization induced by point mutation or monoclonal antibody treatment were also analyzed. ErbB-2 binding to peptides containing the Src homology 2 domain of Grb2 or p85 and the phosphotyrosine binding domain of Shc varies according to the mode of receptor activation. Finally, tryptic phosphopeptide mapping of both ErbB-1 and ErbB-2 reveals that receptor phosphorylation is dependent on the dimerization partner. Differential receptor phosphorylation may, therefore, be the basis for the differences in the signaling properties observed (Olayioye, 1988).

Neuregulin, neurite extension and axon guidance

Neuregulin-1 (NRG-1) growth and differentiation factors and their erbB receptors are hypothesized to promote embryonic hippocampal neuron differentiation via as yet unknown mechanisms. NRG-1beta increases the outgrowth of primary neurites, neuronal area, total neurite length, and neuritic branching in E18 hippocampal neurons. NRG-1beta effects on neurite extension and arborization are similar to, but not additive with, those of brain-derived neurotrophic factor and reflect direct NRG-1 action on hippocampal neurons since these cells express the NRG-1 receptors erbB2 and erbB4. The erbB-specific inhibitor PD158780 decreases NRG-1beta induced neurite outgrowth, and NRG-1beta stimulation induces p42/44 ERK phosphorylation. Pharmacological inhibition of p42/44 ERK and protein kinase C (PKC), but not PI3K or p38 MAP kinase, inhibits NRG-1beta-induced neurite extension and elaboration. It is concluded that NRG-1beta stimulates hippocampal neurite extension and arborization via a signaling pathway that involves erbB membrane tyrosine kinases (erbB2 and/or erbB4), p42/44 ERK, and PKC (Gerecke, 2004).

Most cortical interneurons arise from the subcortical telencephalon, but the molecules that control their migration remain largely unidentified. Different isoforms of Neuregulin-1 are expressed in the developing cortex and in the route that migrating interneurons follow toward the cortex, whereas a population of the migrating interneurons express ErbB4, a receptor for Neuregulin-1. The different isoforms of Neuregulin-1 act as short- and long-range attractants for migrating interneurons, and perturbing ErbB4 function in vitro decreases the number of interneurons that tangentially migrate to the cortex. In vivo, loss of Neuregulin-1/ErbB4 signaling causes an alteration in the tangential migration of cortical interneurons and a reduction in the number of GABAergic interneurons in the postnatal cortex. These observations provide evidence that Neuregulin-1 and its ErbB4 receptor directly control neuronal migration in the nervous system (Flames, 2004).

Neuronal migration and axon guidance constitute fundamental processes in brain development that are generally studied independently. Although both share common mechanisms of cell biology and biochemistry, little is known about their coordinated integration in the formation of neural circuits. This study shows that the development of the thalamocortical projection, one of the most prominent tracts in the mammalian brain, depends on the early tangential migration of a population of neurons derived from the ventral telencephalon. This tangential migration contributes to the establishment of a permissive corridor that is essential for thalamocortical axon pathfinding. The results also demonstrate that in this process two different products of the Neuregulin-1 gene, CRD-NRG1 and Ig-NRG1, mediate the guidance of thalamocortical axons. These results show that neuronal tangential migration constitutes a novel mechanism to control the timely arrangement of guidance cues required for axonal tract formation in the mammalian brain (Lopez-Bendito, 2006).

Neuregulin and ensheathment of axons

The signals that determine whether axons are ensheathed or myelinated by Schwann cells have long been elusive. Threshold levels of neuregulin-1 (NRG1) type III on axons determine their ensheathment fate. Ensheathed axons express low levels whereas myelinated fibers express high levels of NRG1 type III. Sensory neurons from NRG1 type III deficient mice are poorly ensheathed and fail to myelinate; lentiviral-mediated expression of NRG1 type III rescues these defects. Expression also converts the normally unmyelinated axons of sympathetic neurons to myelination. Nerve fibers of mice haploinsufficient for NRG1 type III are disproportionately unmyelinated, aberrantly ensheathed, and hypomyelinated, with reduced conduction velocities. Type III is the sole NRG1 isoform retained at the axon surface and activates PI 3-kinase, which is required for Schwann cell myelination. These results indicate that levels of NRG1 type III, independent of axon diameter, provide a key instructive signal that determines the ensheathment fate of axons (Taveggia, 2005).

Proteins encoded by the neuregulin-1 (NRG1) gene are candidate axonal signals for regulating Schwann cell differentiation. At least 15 different secreted or transmembrane NRG1 isoforms resulting from alternative promoter usage and RNA splicing are expressed by neurons and glia, including Schwann cells. These can be classified into three major types (I, II, and III) that differ in their amino terminal sequences. Each isoform contains an EGF domain that is sufficient to activate their cognate receptors, members of the erbB family. NRG1 type III is the major isoform expressed by neurons that project into the PNS (Taveggia, 2005).

NRG1 has a key role at many stages of the Schwann cell lineage. These include promoting commitment of neural crest cells to the glial lineage and the proliferation, survival, and maturation of Schwann cells and their precursors. Striking confirmation of NRG1's importance in the Schwann cell lineage is evidenced by the severe deficiency of Schwann cells in mice with targeted disruptions of the NRG1 gene or its receptors. Isoform-specific NRG1 knockouts, and the pattern of expression, provide compelling evidence that type III is the key isoform required for Schwann cell generation (Taveggia, 2005).

The role of NRG1 in regulating axon ensheathment and myelination by Schwann cells has remained elusive. Analysis has been complicated by the failure of Schwann cells to develop in mice with targeted mutations of NRG1 and its receptors, together with the embryonic lethality of these mice. Recent studies using transgenic and conditional knockout strategies have established that levels of axonal NRG1, signaling through the erbB2 coreceptor, determine the number of lamellae that myelinating Schwann cells form around axons. A fundamental unanswered question is whether NRG1 also dictates the binary choice of axon ensheathment fates by regulating the alternative phenotypes of Schwann cells. This study reports that threshold levels of NRG1 type III, independent of axon diameter, provide the long-sought instructive signal that determines whether axons become ensheathed or myelinated (Taveggia, 2005).

Understanding the control of myelin formation by oligodendrocytes is essential for treating demyelinating diseases. Neuregulin-1 (NRG1) type III, an EGF-like growth factor, is essential for myelination in the PNS. It is thus thought that NRG1/ErbB signaling also regulates CNS myelination, a view suggested by in vitro studies and the overexpression of dominant-negative ErbB receptors. To directly test this hypothesis, a series of conditional null mutants was generated that completely lack NRG1 beginning at different stages of neural development. Unexpectedly, these mice assemble normal amounts of myelin. In addition, double mutants lacking oligodendroglial ErbB3 and ErbB4 become myelinated in the absence of any stimulation by neuregulins. In contrast, a significant hypermyelination is achieved by transgenic overexpression of NRG1 type I or NRG1 type III. Thus, NRG1/ErbB signaling is markedly different between Schwann cells and oligodendrocytes that have evolved an NRG/ErbB-independent mechanism of myelination control (Brinkmann, 2008).

During peripheral nerve development, each segment of a myelinated axon is matched with a single Schwann cell. Tight regulation of Schwann cell movement, proliferation and differentiation is essential to ensure that these glial cells properly associate with axons. ErbB receptors are required for Schwann cell migration, but the operative ligand and its mechanism of action have remained unknown. This study demonstrates that zebrafish Neuregulin 1 (Nrg1) type III, which signals through ErbB receptors, controls Schwann cell migration in addition to its previously known roles in proliferation and myelination. Chimera analyses indicate that ErbB receptors are required in all migrating Schwann cells, and that Nrg1 type III is required in neurons for migration. Surprisingly, expression of the ligand in a few axons is sufficient to induce migration along a chimeric nerve constituted largely of nrg1 type III mutant axons. These studies also reveal a mechanism that allows Schwann cells to fasciculate axons regardless of nrg1 type III expression. Time-lapse imaging of transgenic embryos demonstrated that misexpression of human NRG1 type III results in ectopic Schwann cell migration, allowing them to aberrantly enter the central nervous system. These results demonstrate that Nrg1 type III is an essential signal that controls Schwann cell migration to ensure that these glia are present in the correct numbers and positions in developing nerves (Perlin, 2011).

Neuregulin and the synapse

Skeletal muscle ACh receptors (AChRs) accumulate at neuromuscular junctions (nmjs) at least partly because of the selective induction of AChR subunit genes in subsynaptic myotube nuclei by the motor nerve terminal. Additionally, mammalian AChRs undergo a postnatal change in subunit composition from embryonic (alpha 2 beta gamma delta) to adult (alpha 2 beta epsilon delta) forms, a switch that also depends on innervation. Based on its ability to induce AChR synthesis in primary chick muscle cells, ARIA (a protein purified from chicken brains) is a strong candidate for being the molecule responsible for these early developmental events. ARIA mRNA has been detected in embryonic motor neurons during synapse formation, and the gene continues to be expressed postnatally. Evidence is provided that ARIA-like immunoreactivity is concentrated in rat motor nerve terminals from early postnatal ages, and that it can be detected in motor neurons in E18 embryos. ARIA is also detectable in axons within colchicine-treated sciatic nerves, suggesting that the protein in the nerve terminal has been transported from the cell body. ARIA mRNA is present in, but not restricted to, cholinergic neurons. Likewise, ARIA-like immunoreactivity is present in some noncholinergic central synapses. Evidence is presented that isoforms of ARIA are differentially distributed among functionally distinct classes of neurons (Sandrock (1995).

ARIA (for acetylcholine receptor-inducing activity), a protein purified on the basis of its ability to stimulate acetylcholine receptor (AChR) synthesis in cultured myotubes, is a member of the neuregulin family and is present at motor endplates. This suggests an important role for neuregulins in mediating the nerve-dependent accumulation of AChRs in the postsynaptic membrane. Nerve-muscle synapses have now been analyzed in neuregulin-deficient animals. Mice that are heterozygous for the deletion of neuregulin isoforms containing an immunoglobulin-like domain are myasthenic. Postsynaptic AChR density is significantly reduced, as judged by the decrease in the mean amplitude of spontaneous miniature endplate potentials and bungarotoxin binding. However, the mean amplitude of evoked endplate potentials is not decreased, due to an increase in the number of quanta released per impulse, a compensation that has been observed in other myasthenic states. Thus, the density of AChRs in the postsynaptic membrane depends on immunoglobulin-containing neuregulin isoforms throughout the life of the animal (Sandrock, 1997).

Developing motor axons induce synaptic specializations in muscle fibers, including preferential transcription of acetylcholine receptor (AChR) subunit genes by subsynaptic nuclei. One candidate nerve-derived signaling molecule is AChR-inducing activity (ARIA)/heregulin, a ligand of the erbB family of receptor tyrosine kinases. It was asked whether ARIA and erbB kinases are expressed in patterns compatible with their proposed signaling roles. In developing muscle, ARIA is present not only at synaptic sites, but also in extrasynaptic regions of the muscle fiber. ARIA is synthesized, rather than merely taken up, by muscle cells, as indicated by the presence of ARIA mRNA in muscle and of ARIA protein in a clonal muscle cell line. ARIA-responsive myotubes express both erbB2 and erbB3, but little EGFR/erbB1 or erbB4. In adults, erbB2 and erbB3 are localized to the postsynaptic membrane. ErbB3 is restricted to the postsynaptic membrane perinatally, at a time when ARIA is still broadly distributed. Thus, these data are consistent with a model in which ARIA interacts with erbB kinases on the muscle cell surface to provide a local signal that induces synaptic expression of AChR genes. However, much of the ARIA is produced by muscle, not nerve, and the spatially restricted response may result from the localization of erbB kinases as well as of ARIA. ErbB3 is not concentrated at synaptic sites in mutant mice that lack rapsyn, a cytoskeletal protein required for AChR clustering, suggesting an interaction between pathways for synaptic AChR expression and clustering (Moscoso, 1995).

Localization of acetylcholine receptors (AChRs) to neuromuscular synapses is mediated by multiple pathways. Agrin, which is the signal for one pathway, stimulates a redistribution of previously unlocalized AChRs to synaptic sites. The signal for a second pathway is not known, but this signal stimulates selective transcription of AChR genes in myofiber nuclei located near the synaptic site. Neuregulin (NRG) is a good candidate for the extracellular signal that induces synapse-specific gene expression, since NRG is concentrated at synaptic sites and activates AChR gene expression in cultured muscle cells. Previous studies have demonstrated that 181 bp of 5' flanking DNA from the AChR delta-subunit gene are sufficient to confer synapse-specific transcription in transgenic mice and NRG responsiveness in cultured muscle cells, but the critical sequences within this cis-acting regulatory region have not been identified. AChR delta-subunit-hGH gene fusions were transfected into a muscle cell line, and it has been shown that a potential binding site for Ets proteins is required for NRG-induced gene expression. Furthermore, transgenic mice were produced carrying AChR delta-subunit-hGH gene fusions with a mutation in this NRG-response element (NRE), and this NRE was shown to be necessary for synapse-specific transcription in mice. The NRE binds proteins in myotube nuclear extracts; nucleotides that are important for NRG responsiveness are likewise critical for formation of the protein-DNA complex. This complex contains GABPalpha, an Ets protein, and GABPbeta, a protein that lacks an Ets domain but dimerizes with GABPalpha, because formation of the protein-DNA complex is inhibited by antibodies to either GABPalpha or GABPbeta. These results demonstrate that synapse-specific and NRG-induced gene expression require an Ets-binding site and suggest that GABPalpha/GABPbeta mediates the transcriptional response of the AChR delta-subunit gene to synaptic signals, including NRG (Fromm, 1998).

Neuregulin-1 (NRG-1) signaling has been implicated in inductive interactions between pre- and postsynaptic partners during synaptogenesis. All identified NRG-1 isoforms can be broadly classified into two mutually exclusive categories: type I and II isoforms, which contain an immunoglobulin- (Ig-) like domain (Ig-NRGs), and type III isoforms, which contain a cysteine-rich domain (CRD-NRGs) N-terminal to a common epidermal growth factor-like sequence. Gene targeting was used to selectively disrupt cysteine-rich domain- (CRD-) containing NRG-1 isoforms. In CRD-NRG-1-/- mice, peripheral projections defasciculate and display aberrant branching patterns within their targets. Motor nerve terminals are transiently associated with broad bands of postsynaptic ACh receptor clusters. Initially, Schwann cell precursors accompany peripheral projections, but later, Schwann cells are absent from axons in the periphery. Following initial stages of synapse formation, sensory and motor nerves withdraw and degenerate. These data demonstrate the essential role of CRD-NRG-1-mediated signaling for coordinating nerve, target, and Schwann cell interactions in the normal maintenance of peripheral synapses, and ultimately in the survival of CRD-NRG-1-expressing neurons (Wolpowitz, 2000).

Neuregulins (NRGs) and their receptors, the ErbB protein tyrosine kinases, are essential for neuronal development, but their functions in the adult CNS are unknown. The neuregulin receptor ErbB4 is enriched in the postsynaptic density (PSD) and associates with PSD-95. Heterologous expression of PSD-95 enhances NRG activation of ErbB4 and MAP kinase. Conversely, inhibiting expression of PSD-95 in neurons attenuates NRG-mediated activation of MAP kinase. PSD-95 forms a ternary complex with two molecules of ErbB4, suggesting that PSD-95 facilitates ErbB4 dimerization. NRG suppresses induction of long-term potentiation in the hippocampal CA1 region without affecting basal synaptic transmission. Thus, NRG signaling may be synaptic and regulated by PSD-95. A role of NRG signaling in the adult CNS may be modulation of synaptic plasticity (Huang, 2000).

In the CA1 region of the hippocampus, a brief train of high-frequency stimulation produces the lasting enhancement of synaptic transmission known as LTP. Stimulation of the NMDA class of glutamate receptors is a key step in the mechanism of LTP. The findings that NRG suppresses induction of LTP in CA1 but has no effect on paired-pulse facilitation together with the localization of ErbB4 in the PSDs suggest that NRG acts via a postsynaptic mechanism. The activity of NMDARs is subject to modulation by tyrosine phosphorylation, but the suppression of LTP could not be attributed to an effect on the amplitude of NMDA currents because NRG does not alter NMDA receptor–mediated synaptic responses. Thus, NRG/ErbB4 signaling may interrupt LTP induction at a step beyond NMDAR stimulation. ErbB4 has an extended C-terminal region that contains numerous tyrosine residues. Upon phosphorylation, these tyrosine residues bind to adapter proteins and activate a diversity of signaling pathways including ERK, JNK, and PI3 kinase. One of these kinase signaling cascades may have a role in the suppression of synaptic plasticity by NRG (Huang, 2000).

NRG-2 and NRG-3 are expressed in adult hippocampus. At the cellular level, nrg mRNAs are detected in granule cells of the hippocampus and the dentate gyrus. There are at least 14 different splice variants of the nrg-1 mRNAs that encode proteins containing an alpha- or beta-type epidermal growth factor (EGF) domain and either an immunoglobulin- (Ig-)like domain or a cysteine-rich domain (CRD) at the N terminus. The Ig-containing, but not CRD-containing, NRG-1 is expressed in adult hippocampus. All NRG functions known to date can be duplicated by the EGF domain. The NRG used in this study, rHRGbeta177–244, is a recombinant polypeptide containing the entire EGF domain (amino acids 177–244) of the beta-type NRG-1, a potent isoform. rHRGbeta177–244 binds to ErbB3 and ErbB4 and thus induces tyrosine phosphorylation of ErbB2, ErbB3, and ErbB4, but not of the EGF receptor. Thus, the effect of rHRGbeta177–244 on LTP is believed to be mediated via activation of the NRG signaling pathway. Exactly which NRGs or NRG isoforms are involved in this event requires further studies (Huang, 2000).

Neuregulins and their Erbb receptors have been implicated in neuromuscular synapse formation by regulating gene expression in subsynaptic nuclei. To analyze the function of Erbb2 in this process, the Erbb2 gene was inactivated in developing muscle fibers by Cre/Lox-mediated gene ablation. Neuromuscular synapses form in the mutant mice, but the synapses are less efficient and contain reduced levels of acetylcholine receptors. Surprisingly, the mutant mice also show proprioceptive defects caused by abnormal muscle spindle development. Sensory Ia afferent neurons establish initial contact with Erbb2-deficient myotubes. However, functional spindles never develop. Taken together, these data suggest that Erbb2 signaling regulates the formation of both neuromuscular synapses and muscle spindles (Leu, 2003).

The data show that Erbb2 expression in skeletal muscle fibers is essential for muscle spindle development. Studies have provided strong evidence that muscle spindle development is initiated by a signal from sensory Ia afferent neurons. Contact of Ia afferents with myotubes is initiated in the absence of Erbb2 expression in myotubes, but muscle spindle formation does not progress and the rudimentary spindles degenerate. This suggests that Erbb2 is not required for the establishment of the initial contact between sensory neurons and myotubes, but for the subsequent differentiation of muscle spindles. Interestingly, during development of sympathetic neurons, NT3 expression is activated by Nrg1. Likewise, muscle spindles express NT3 and muscle spindles are absent in NT3-deficient mice. This raises the possibility that NT3 is more generally a downstream effector of Nrg1/Erbb signaling, and that it is an essential component by which Erbb2 regulates muscle spindle development. In this model, activation of Erbb2 in muscle fibers may regulate expression of NT3. Since NT3 promotes survival of Ia afferent neurons, and because ectopic expression of Ntf3 induces muscle spindle development, Nrg1/Erbb signaling may be essential to maintain NT3 expression in muscle spindles during their development, which in turn may affect sensory Ia afferent neurons. Since the zinc-finger transcription factor Egr3 appears to regulate spindle specific NT3 expression, and is essential for muscle spindle maintenance, it is possible that Erbb2 may act at least in part upstream of Egr3 thereby regulating NT3 expression (Leu, 2003).

Acetylcholine receptor (AChR) genes are transcribed selectively in synaptic nuclei of skeletal muscle fibers, leading to accumulation of the mRNAs encoding AChR subunits at synaptic sites. The signals that regulate synapse-specific transcription remain elusive, though Neuregulin-1 is considered a favored candidate. Motor neurons and terminal Schwann cells express neuregulin-2, a neuregulin-1-related gene. In skeletal muscle, Neuregulin-2 protein is concentrated at synaptic sites, where it accumulates adjacent to terminal Schwann cells. Neuregulin-2 stimulates AChR transcription in cultured myotubes expressing ErbB4, as well as ErbB3 and ErbB2, but not in myotubes expressing only ErbB3 and ErbB2. Thus, Neuregulin-2 is a candidate for a signal that regulates synaptic differentiation (Rimer, 2004).

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