Effects Of Neuregulin-1 Research Articles

Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins

Neuregulin-1 (NRG1) is a potential therapeutic agent for the treatment of doxorubicin (Dox)-induced heart failure. NRG1, however, activates the erbB2 receptor, which is frequently overexpressed in breast cancers. It is, therefore, important to understand how NRG1, via erbB2, protects the heart against Dox cardiotoxicity. Here, we studied NRG1-erbB2 signaling in Dox-treated mice hearts and in isolated neonatal rat ventricular myocytes (NRVM). Male C57BL/6 mice were treated with recombinant NRG1 before and daily after a single dose of Dox. Cardiac function was determined by catheterization. Two-week survival was analyzed by the Kaplan-Meier method. Cardiac troponins [cardiac troponin I (cTnI) and cardiac troponin T (cTnT)] and phosphorylated Akt protein levels were determined in mice hearts and in NRVM by Western blot analysis. Activation of caspases and ubiquitinylation of troponins were determined in NRVM by caspase assay and immunoprecipitation. NRG1 significantly improved survival and cardiac function in Dox-treated mice. NRG1 reduced the decrease in cTnI, cTnT, and cardiac troponin C (cTnC) and maintained Akt phosphorylation in Dox-treated mice hearts. NRG1 reduced the decrease in cTnI and cTnT mRNA and proteins in Dox-treated NRVM. Inhibition of erbB2, phosphoinositide 3-kinase (PI3K), Akt, and mTOR blocked the protective effects of NRG1 on cTnI and cTnT in NRVM. NRG1 significantly reduced Dox-induced caspase activation, which degraded troponins, in NRVM. NRG1 reduced Dox-induced proteasome degradation of cTnI. NRG1 attenuates Dox-induced decrease in cardiac troponins by increasing transcription and translation and by inhibiting caspase activation and proteasome degradation of troponin proteins. NRG1 maintains cardiac troponins by the erbB2-PI3K pathway, which may lessen Dox-induced cardiac dysfunction.

Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia

Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/−), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/− pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling.

Effects of Neuregulin on Expression of MMP-9 and NSE in Brain of Ischemia/Reperfusion Rat

The aim is to investigate the effects of neuregulin-1beta (NRG-1beta) on expression of matrix metalloproteinase-9 (MMP-9) and neuron-specific enolase (NSE) in brain tissue in rats following cerebral ischemia/reperfusion. One hundred and fifty adult healthy male Wistar rats were used in the present study. Ten of them were randomized into a sham-operation group (n = 10) and the rest suffered surgery operation of middle cerebral artery occlusion/reperfusion with intraluminal monofilament suture from the left external-internal carotid artery. As a result, 100 rats of successful models were randomly divided into a control group (n = 50) and a treatment group (n = 50). Rats in the treatment group were injected 1.5% NRG-1beta at a dosage of 0.3 microg/kg from the stump of the left external carotid artery into the internal carotid artery. The expressions of MMP-9 and NSE proteins were determined by immunohistochemical, immunofluorescent double labeling, and Western blot assay. Ischemia/reperfusion induced morphological changes of brain tissue, including neurocyte shrinkage, chromatin condensation, nuclei fragment, and gliacyte and endothelial cell swelling. NRG-1beta obviously reduced and delayed the cerebral damage. With the duration of ischemia, the expression of MMP-9 gradually increased in the control group. NRG-1beta decreased the level of MMP-9 compared with that in the control group (P < 0.01). NSE immunoreaction transiently elevated at the early stage of cerebral ischemia insult, and then gradually decreased in the control group. The administration of NRG-1beta significantly increased the level of NSE, and thus delayed the time and the degree of neuron damage. There were statistical differences in contrast to the control group (P < 0.01). There was no relationship between the expressions of the two proteins. MMP-9 might aim at various target cells at different stages and contribute to the inflammatory reaction after cerebral ischemia-reperfusion insult. NRG-1beta inhibits the activation of MMP-9 and development of inflammation, enhances the activity of NSE, improves the microenvironment of neuron survivals, and delays the phase of irreversible neuron necrosis. Therefore, NRG-1beta may play a neuroprotective role in cerebral ischemia/reperfusion.

Effect of Neuregulin on Apoptosis and Expressions of STAT3 and GFAP in Rats Following Cerebral Ischemic Reperfusion

The aim is to investigate the effect of neuregulin-1beta (NRG-1beta) on the neuronal apoptosis and the expressions of signal transducer and activator of transcription (STAT3) and glial fibrillary acidic protein (GFAP) in rats following cerebral ischemia/reperfusion. The animal models of middle cerebral artery occlusion/reperfusion (MCAO/R) were established by an intraluminal filament method from left external-internal carotid artery in 100 cases of adult healthy male Wister rats. NRG-1beta was administered from the internal carotid artery (ICA) into MCA in the treatment group. The neuronal apoptosis was detected by terminal deoxynucleotidyl transference-mediated biotinylated deoxyuridine triphosphate nick-end labeling technique. The expression alternations of STAT3 and GFAP proteins were determined by fluorescent labeling analysis and Western blotting assay. Ischemic cerebral injury could induce neuronal apoptosis. Furthermore, with the duration of ischemia, the amount of apoptotic cells increased in the control group. These apoptotic cells distributed in various brain regions, especially the cortex, striatum, and hippocampus, while only a small amount of apoptotic cells could be observed in the treatment group, and there were significant differences compared with that in the control group (P < 0.01). The expressions of STAT3 and GFAP proteins in brain tissue gradually increased in the control group with the duration of ischemia. And NRG-1beta could elevate the expressional level of STAT3 and GFAP proteins in contrast to the control group (P < 0.05). NRG-1beta may play a neuroprotective role in cerebral ischemic insult by activating JAK/STAT signal transduction pathway, promoting the astrocyte gumnosis and regulating the anti-apoptosis mechanism in neurocytes.

The effects of neuregulin1 on brain function in controls and patients with schizophrenia and bipolar disorder

Recent studies have identified neuregulin1 as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders. The present investigation examined the impact of neuregulin1 genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 115 subjects comprising 41 patients with schizophrenia, 29 patients with bipolar disorder and 45 healthy volunteers. We then used statistical parametric mapping to estimate the main effects of diagnostic group, the main effect of genotype and their interaction. We tested the hypothesis that the high-risk variant of neuregulin1 would be associated with altered prefrontal function. In all three diagnostic groups, the high-risk variant of neuregulin1 was associated with greater deactivation in the left precuneus. In addition, there was an interaction between diagnosis and genotype in two regions of the prefrontal cortex. The right inferior frontal gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with schizophrenia. Conversely, the right posterior orbital gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with bipolar disorder. Our results suggest that genetic variation in neuregulin1 has a measurable impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in different regions of the prefrontal cortex.

ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration

The cellular events that precede myelination in the peripheral nervous system require rapid and dynamic morphological changes in the Schwann cell. These events are thought to be mainly controlled by axonal signals. But how signals on the axons are coordinately organized and transduced to promote proliferation, migration, radial sorting, and myelination is unknown. We describe that the axonal signal neuregulin-1 (NRG1) controls Schwann cell migration via activation of the atypical Dock180-related guanine nucleotide exchange factor (GEF) Dock7 and subsequent activation of the Rho guanine triphosphatases (GTPases) Rac1 and Cdc42 and the downstream c-Jun N-terminal kinase. We show that the NRG1 receptor ErbB2 directly binds and activates Dock7 by phosphorylating Tyr-1118. Dock7 knockdown, or expression of Dock7 harboring the Tyr-1118–to–Phe mutation in Schwann cells, attenuates the effects of NRG1. Thus, Dock7 functions as an intracellular substrate for ErbB2 to promote Schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of Rho GTPase-GEFs of the Dock180 family.

Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia

We previously showed that neuregulin-1 (NRG-1) protected neurons from death in vivo following focal ischemia. The goal of this study was to develop an in vitro rat ischemia model to examine the cellular and molecular mechanisms involved in the neuroprotective effects of NRG-1 on ischemia-induced neuronal death. Rat B-35 neuroblastoma cells differentiated by serum withdrawal, developed enhanced neuronal characteristics including, neurite extension and upregulation of neuronal markers of differentiation. When B35 neurons were subjected to oxygen glucose deprivation (OGD)/reoxygenation or glutamate, widespread neuronal death was seen after both treatments. Treatment with NRG-1 immediately after OGD significantly increased neuronal survival. NRG-1 administration also resulted in a significant decrease in annexin V, an early marker of apoptosis. However, the neurotoxic actions of glutamate were unaffected by NRG-1. The neuroprotective effects of NRG-1 were prevented by an inhibitor of the phosphatidylinositol-3-kinase/Akt pathway. These results provide a new model to gain insight into the mechanisms employed by NRG-1 to protect neurons from ischemic brain injury.

Spinal cord hemisection disrupts descending neuregulin input to phrenic motoneurons

Spinal cord hemisection at C2 (SH) disrupts descending drive to ipsilateral phrenic motoneurons (PMNs) causing unilateral diaphragm muscle (DIAm) paralysis. Previously, we found a decrease in motoneuron size at 2 weeks post‐SH. Recently, we found neuregulin (NRG) in synaptic boutons surrounding PMNs. NRG is a trophic factor known to regulate development of the neuromuscular junction, but the effect of NRG on motoneurons is unknown. We hypothesized that 1) NRG input to PMNs is supraspinal in origin, and 2) SH disrupts NRG input to PMNs. Adult male Sprague‐Dawley rats underwent SH or sham‐surgery. PMNs were retrogradely labeled by intramuscular injection of Alexa488‐conjugated cholera toxin B. Using laser capture microdissection, we found that PMNs express mRNA for the NRG receptors ErbB2 and ErbB3, providing a functional substrate for a NRG effect. Two weeks post‐SH, labeled PMNs and NRG boutons were imaged using confocal microscopy. PMN morphology and the number of NRG boutons in the vicinity of PMNs were determined using a computerized, semi‐automated reconstruction algorithm. NRG boutons were fairly homogeneously distributed on motoneurons independent of size. Following SH, few NRG boutons were observed. We conclude that 1) NRG input to PMNs derives from a supraspinal source; and 2) SH removes NRG input to PMNs. It is possible that NRG input exerts a trophic influence on PMNs.Supported by NIH grants HL37680, AR51173 and Mayo Clinic

168 – Confirmation of the association of the neuregulin 1 gene (NRG1) with schizophrenia in a human isolate from northern Spain

Neuregulin-1 (NRG-1) is a growth factor with potent neuroprotective capacity in ischemic stroke. We recently showed that NRG-1 reduced neuronal death following transient middle cerebral artery occlusion (tMCAO) by up to 90% with an extended therapeutic window. Here, we examined the neuroprotective potential of NRG-1 using a permanent MCAO ischemia (pMCAO) rat model. NRG-1 reduced infarction in pMCAO by 50% when administered prior to ischemia. We previously demonstrated using gene expression profiling that pMCAO was associated with an exaggerated excitotoxicity response compared to tMCAO. Therefore, we examined whether co-treatment with an inhibitor of excitotoxicity would augment the effect of NRG-1 following pMCAO. Both NRG-1 and the N-methyl-d-aspartate (NMDA) antagonist MK-801 similarly reduced infarct size following pMCAO. However, combination treatment with both NRG-1 and MK-801 resulted in greater neuroprotection than either compound alone, including a 75% reduction in cortical infarction compared to control. Consistent with these findings, NRG-1 reduced neuronal death using an in vitro ischemia model and this effect was augmented by MK-801. These results demonstrate the efficacy of NRG-1 in pMCAO rat focal ischemia model. Our findings further indicate the potential clinically relevance of NRG-1 alone or as a combination strategy for treating ischemic stroke.

Effect of Neuregulin-1 on Histopathological and Functional Outcome after Controlled Cortical Impact in Mice

Neuregulin-1 is a pleiotropic endogenous growth factor that is neuroprotective in experimental models of cerebral ischemia. We tested the hypothesis that pretreatment with neuregulin-1 would be similarly protective after traumatic brain injury in mice. Mice were administered neuregulin-1 or equal amounts of vehicle intravenously immediately before controlled cortical impact. Injured mice were subjected to motor and cognitive testing, and brain tissue loss was quantitated at 4 weeks. Compared to vehicle, pretreatment with neuregulin-1 had no effect on brain tissue loss, motor function, or acquisition of a spatial learning task. However, neuregulin-1 treated mice showed improved retention of spatial memory versus vehicle-treated mice in subsequent probe trials (p<0.05). These proof-of-principle data suggest that neuregulin-1 may improve some functional outcomes after brain trauma. Further studies are therefore warranted to more carefully explore molecular mechanisms, dose-responses, and relationships between morphological outcome and long-term recovery.

The effects of a neuregulin 1 variant on white matter density and integrity

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia

Neuregulin-1 (NRG-1) is a growth factor with potent neuroprotective capacity in ischemic stroke. We recently showed that NRG-1 reduced neuronal death following transient middle cerebral artery occlusion (tMCAO) by up to 90% with an extended therapeutic window. Here, we examined the neuroprotective potential of NRG-1 using a permanent MCAO ischemia (pMCAO) rat model. NRG-1 reduced infarction in pMCAO by 50% when administered prior to ischemia. We previously demonstrated using gene expression profiling that pMCAO was associated with an exaggerated excitotoxicity response compared to tMCAO. Therefore, we examined whether co-treatment with an inhibitor of excitotoxicity would augment the effect of NRG-1 following pMCAO. Both NRG-1 and the N-methyl-D-aspartate (NMDA) antagonist MK-801 similarly reduced infarct size following pMCAO. However, combination treatment with both NRG-1 and MK-801 resulted in greater neuroprotection than either compound alone, including a 75% reduction in cortical infarction compared to control. Consistent with these findings, NRG-1 reduced neuronal death using an in vitro ischemia model and this effect was augmented by MK-801. These results demonstrate the efficacy of NRG-1 in pMCAO rat focal ischemia model. Our findings further indicate the potential clinically relevance of NRG-1 alone or as a combination strategy for treating ischemic stroke.

Role of Neuregulin-1/ErbB Signaling in Cardiovascular Physiology and Disease

Since the discovery that neuregulin-1 (NRG-1)/ErbB signaling is indispensable in cardiac development, evidence has shown that this system also plays a crucial role in the adult heart. In patients, an inhibitory ErbB2 antibody, trastuzumab, used in the treatment of mammary carcinomas, increases the risk for the development of cardiotoxic cardiomyopathy. Postnatal disruption of NRG-1/ErbB signaling by gene targeting in mice leads to dilated cardiomyopathy. Initially, the search for the mechanisms behind these observations focused mainly on the effects of NRG-1 on cardiomyocyte growth and survival and revealed that NRG-1 has Akt-dependent antiapoptotic effects in cultured cardiomyocytes. In vivo studies, however, did not uniformly reinforce a role for apoptosis in the development of cardiomyopathy induced by impaired NRG-1/ErbB signaling. More recent studies have revealed that NRG-1 is involved in the regulation of cardiac sympathovagal balances by counterbalancing adrenergic stimulation of the adult myocardium and through an obligatory interaction with the muscarinic cholinergic system. NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium, dynamically controlled by neurohormonal and biomechanical stimuli. The physiology of the cardiac NRG-1/ErbB system has implications for the treatment of both cancer and heart failure. Clinical studies in breast cancer with novel ErbB inhibitors are currently underway. Novel oncological indications for ErbB inhibition are emerging; cardiovascular side effects need to be carefully monitored. On the other hand, pharmacological activation of ErbB signaling is likely an unrecognized and beneficial effect of currently used drugs in heart failure and a promising therapeutic approach to prevent or reverse myocardial dysfunction.

NRG1 and Synaptic Function in the CNS

Recent genetic evidence indicates that neuregulin 1 (NRG1) and its receptor erbB4 may be susceptibility genes in schizophrenia, but their function in CNS synaptic transmission and circuitry is not well understood. In this issue of Neuron, studies from Li et al. and Woo et al. show that NRG1 and erbB4 regulate transmission at brain glutamate and GABA synapses. These findings raise the possibility of synaptic defects in schizophrenia.

Neuregulin-1 Enhances Depolarization-Induced GABA Release

Neuregulin-1 (NRG1), a regulator of neural development, has been shown to regulate neurotransmission at excitatory synapses. Although ErbB4, a key NRG1 receptor, is expressed in glutamic acid decarboxylase (GAD)-positive neurons, little is known about its role in GABAergic transmission. We show that ErbB4 is localized at GABAergic terminals of the prefrontal cortex. Our data indicate a role of NRG1, both endogenous and exogenous, in regulation of GABAergic transmission. This effect was blocked by inhibition or mutation of ErbB4, suggesting the involvement of ErbB4. Together, these results indicate that NRG1 regulates GABAergic transmission via presynaptic ErbB4 receptors, identifying a novel function of NRG1. Because both NRG1 and ErbB4 have emerged as susceptibility genes of schizophrenia, these observations may suggest a mechanism for abnormal GABAergic neurotransmission in this disorder.

Neuregulin-1 Attenuates Neointimal Formation following Vascular Injury and Inhibits the Proliferation of Vascular Smooth Muscle Cells

Neuregulin-1 (NRG-1) is expressed in vascular endothelial cells, and its receptors are localized to the underlying smooth muscle cells. However, the role of NRG-1 in vascular function and injury is largely unknown. First, the expression of NRG-1 and its receptors (erbB receptors) was analyzed after balloon injury to the rat carotid artery. NRG-1 and erbB expression levels were low in uninjured vessels; however, NRG-1 and erbB4 were upregulated following injury. We then examined the effect of NRG-1 on neointimal formation following balloon injury. NRG-1 was administered by tail-vein injection prior to injury and every 2 days following injury. Two weeks after injury, NRG-1-treated animals demonstrated a 50% reduction in lesion size compared with controls receiving the vehicle. To examine possible mechanisms for NRG-1 action, we examined its effects on vascular smooth muscle cell (VSMC) function. Rat VSMC cultures were pretreated with NRG-1 for 24 h and then stimulated with platelet-derived growth factor. NRG-1 significantly decreased platelet-derived growth factor-stimulated VSMC proliferation and migration. These findings suggest that NRG-1 may be a novel therapeutic candidate for the treatment of restenosis and atherosclerosis.

Role of Neuregulin-1/ErbB2 Signaling in Endothelium-Cardiomyocyte Cross-talk

Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, has been shown to be indispensable for the normal function of the adult heart by binding to ErbB4 receptors on cardiomyocytes. In the present study, we have investigated to what extent ErbB2, the favored co-factor of ErbB4 for heterodimerization, participates in the cardiac effects of endothelium-derived NRG-1. In addition, in view of our previously described anti-adrenergic effects of NRG-1, we have studied which neurohormonal stimuli affect endothelial NRG-1 expression and release and how this may fit into a broader frame of cardiovascular physiology. Immunohistochemical staining of rat heart and aorta showed that NRG-1 expression was restricted to the endocardial endothelium and the cardiac microvascular endothelium (CMVE); by contrast, NRG-1 expression was absent in larger coronary arteries and veins and in aortic endothelium. In rat CMVE in culture, NRG-1 mRNA and protein expression was down-regulated by angiotensin II and phenylephrine and up-regulated by endothelin-1 and mechanical strain. CMVE-derived NRG-1 was shown to phosphorylate cardiomyocyte ErbB2, an event prevented by a 24-h preincubation of myocytes with monoclonal ErbB2 antibodies. Pretreating cardiomyocytes with these inhibitory anti-ErbB2 antibodies significantly attenuated CMVE-induced cardiomyocyte hypertrophy and abolished the protective actions of CMVE against cardiomyocyte apoptosis. Accordingly, ErbB2 signaling participated in the paracrine survival and growth controlling effects of NRG-1 on cardiomyocytes in vitro, explaining the cardiotoxicity of ErbB2 antibodies in patients. Cardiac NRG-1 synthesis occurs in endothelial cells adjacent to cardiac myocytes and is sensitive to factors related to the regulation of blood pressure.

Neuregulin 1–erbB Signaling Is Necessary for Normal Myelination and Sensory Function

To investigate the role of erbB signaling in the interactions between peripheral axons and myelinating Schwann cells, we generated transgenic mice expressing a dominant-negative erbB receptor in these glial cells. Mutant mice have delayed onset of myelination, thinner myelin, shorter internodal length, and smaller axonal caliber in adulthood. Consistent with the morphological defects, transgenic mice also have slower nerve conduction velocity and defects in their responses to mechanical stimulation. Molecular analysis indicates that erbB signaling may contribute to myelin formation by regulating transcription of myelin genes. Analysis of sciatic nerves showed a reduction in the levels of expression of myelin genes in mutant mice. In vitro assays revealed that neuregulin-1 (NRG1) induces expression of myelin protein zero (P0). Furthermore, we found that the effects of NRG1 on P0 expression depend on the NRG1 isoform used. When NRG1 is presented to Schwann cells in the context of cell-cell contact, type III but not type I NRG1 regulates P0 gene expression. These results suggest that disruption of the NRG1-erbB signaling pathway could contribute to the pathogenesis of peripheral neuropathies with hypomyelination and neuropathic pain.

Interactions between β‐neuregulin and neurotrophins in motor neuron apoptosis

Neuregulins play a major role in the formation and stabilization of neuromuscular junctions, and are produced by both motor neurons and muscle. Although the effects and mechanism of neuregulins on skeletal muscle (e.g. regulation of acetylcholine receptor expression) have been studied extensively, the effects of neuregulins on motor neurons remain unknown. We report that neuregulin-1beta (NRGbeta1) inhibited apoptosis of rat motor neurons for up to 7 days in culture by a phosphatidylinositol 3 kinase-dependent pathway and synergistically enhanced motor neuron survival promoted by glial-derived neurotrophic factor (GDNF). However, binding of neurotrophins, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), to the p75 neurotrophin receptor (p75NTR) abolished the neuregulin anti-apoptotic effect on motor neurons. Inhibitors of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase prevented motor neuron death caused by co-incubation of NRGbeta1 and BDNF or NGF, as well as by trophic factor deprivation. Motor neuron apoptosis resulting from both trophic factor deprivation and exposure to NRGbeta1 plus neurotrophins required the induction of neuronal nitric oxide synthase and peroxynitrite formation. Because motor neurons express both p75NTR and neuregulin erbB receptors during the period of embryonic programmed cell death, motor neuron survival may be the result of complex interactions between trophic and death factors, which may be the same molecules acting in different combinations.

Agrin Yes, Neuregulin No

Neuromuscular junctions develop through a series of reciprocal interactions between the muscle fiber and the incoming motor neuron. Both agrin and neuregulin have been implicated in neuromuscular junction development. Escher et al. use targeted gene ablations to clarify which molecules act when. It seems that neuregulins are not critical for neuromuscular junction formation but agrin is. The previously observed effects of neuregulin signaling disruptions on neuromuscular junction formation may well have been mediated indirectly through the effects of neuregulins on Schwann cells, which surround the neuromuscular junction. P. Escher, E. Lacazette, M. Courtet, A. Blindenbacher, L. Landmann, G. Bezakova, K. C. Lloyd, U. Mueller, H. R. Brenner, Synapses form in skeletal muscles lacking neuregulin receptors. Science 308 , 1920-1923 (2005). [Abstract] [Full Text]