Schizophrenia is a highly debilitating mental disorder that affects −1% of the general population, yet it continues to be poorly understood. Recent studies have identified variations in several genes that are associated with this disorder in diverse populations, including those that encode neuregulin 1 (NRG1) and its receptor ErbB4. The past few years have witnessed exciting progress in our knowledge of NRG1 and ErbB4 functions and the biological basis of the increased risk for schizophrenia that is potentially conferred by polymorphisms in the two genes. An improved understanding of the mechanisms by which altered function of NRG1 and ErbB4 contributes to schizophrenia might eventually lead to the development of more effective therapeutics.Schizophrenia is a severe and disabling mental disorder that is characterized by chronic positive symptoms (hallucinations, delusions and thought disorders), negative symptoms (social withdrawal, apathy and emotional blunting) and cognitive deficits. Although schizophrenia is a highly prevalent CNS disorder, it continues to be one of the least understood, primarily owing to its lack of pathological hallmarks. Most, if not all, commonly prescribed antipsychotics are anti-dopaminergic, and their use has been based on the 'classical' dopamine hypothesis, which posits that it is the hyperactivity of dopaminergic transmission that causes positive symptoms 1 . However, current antipsychotics are only modestly effective treatments for the cognitive dysfunction and negative symptoms that are associated with schizophrenia. Moreover, studies on the mechanism of action of antipsychotics have not been particularly informative about the pathogenesis of the disease 2 .Recent genetic studies have provided insight into the possible aetiological mechanisms of this devastating disorder. Schizophrenia has a significant genetic component, and several genes have been associated with the disorder in diverse populations 3 . In particular, the identification of polymorphisms in the genes that encode neuregulin 1 (NRG1) and its receptor ErbB4 has provided a useful starting point from which to better dissect the pathogenic mechanisms of schizophrenia. The past few years have witnessed major progress in our understanding of NRG1 function in neurodevelopment, neurotransmission and synaptic plasticity and of the potential pathological basis of the increased risk that is conferred by polymorphisms in NRG1 and ERBB4. In this Review we briefly discuss the basic signalling machinery of NRG1, review recent findings on the roles of NRG1 and ErbB signalling during development and synaptic plasticity, and explore the implications for the pathophysiology of schizophrenia.Correspondence to: Lin Mei, Email: E-mail: lmei@mcg.edu. NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2009 May 14. Published in final edited form as:Nat Rev Neurosci. 2008 June ; 9(6): 437-452. doi:10.1038/nrn2392. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript NRG1 an...

SUMMARY Formation of the neuromuscular junction (NMJ) requires agrin, a factor released from motoneurons, and MuSK, a transmembrane tyrosine kinase that is activated by agrin. However, how signal is transduced from agrin to MuSK remains unclear. Here we report that low-density lipoprotein receptor (LDLR)-related protein (LRP) 4 (LRP4) functions as a co-receptor of agrin. LRP4 is specifically expressed in myotubes and is concentrated at the NMJ. The extracellular domain of LRP4 interacts with neuronal, but not muscle, agrin. Expression of LRP4 enables agrin binding activity and MuSK signaling in cells that otherwise does not respond to agrin. Suppression of LRP4 expression attenuates agrin binding activity, agrin-induced MuSK tyrosine phosphorylation and AChR clustering in muscle cells. LRP4 also interacts with MuSK in a manner that is stimulated by agrin. Finally, we showed that LRP4 becomes tyrosine-phosphorylated in agrin-stimulated muscle cells. These observations identify LRP4 as a functional co-receptor of agrin that is necessary for agrin-induced MuSK signaling and AChR clustering.

SummarySynapses, as fundamental units of the neural circuitry, enable complex behaviors. The neuromuscular junction (NMJ) is a synapse type that forms between motoneurons and skeletal muscle fibers and that exhibits a high degree of subcellular specialization. Aided by genetic techniques and suitable animal models, studies in the past decade have brought significant progress in identifying NMJ components and assembly mechanisms. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues, which shed light on synaptogenesis in the brain and contribute to a better understanding of muscular dystrophy. Key words: Neural development, Neuromuscular junction, Retrograde signaling, Synapse formation IntroductionThe brain contains billions of nerve cells, or neurons, which receive and integrate signals from the environment, and which govern the body's responses. Nervous system activity is made possible by synapses, contacts formed either between neurons or between a neuron and a target cell. Synapses are asymmetric structures in which neurotransmitter molecules are released from the presynaptic membrane and activate receptors on the postsynaptic membrane, thus establishing neuronal communication. As such, synapses are fundamental units of neural circuitry and enable complex behaviors. The neuromuscular junction (NMJ) is a type of synapse formed between motoneurons and skeletal muscle fibers. Large and easily accessed experimentally, this peripheral synapse has contributed greatly to the understanding of the general principles of synaptogenesis and to the development of potential therapeutic strategies for muscular disorders. The NMJ uses different neurotransmitters in different species; for example, acetylcholine (ACh) in vertebrates and glutamate in Drosophila, both of which are excitatory and cause muscle contraction. In Caenorhabditis elegans, there are two types of NMJs: at excitatory NMJs, ACh causes muscle contraction, whereas inhibitory NMJs release g-aminobutyric acid (GABA) to cause muscle relaxation. Motor nerve terminals differentiate to form presynaptic active zones, where synaptic vesicles dock and release neurotransmitters. On the apposed postsynaptic membranes, neurotransmitter receptors are packed at high densities. Aided by genetic techniques and by the use of suitable animal models, including rodents, zebrafish, Drosophila and C. elegans, studies in the past decade have brought significant progress, not only in identifying components present in pre-and postsynaptic membranes, but also in understanding the mechanisms that underpin NMJ assembly. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues from motor nerves and muscle fibers. Readers are referred to other outstanding reviews for a broad view of NMJ development (see Froehner, 1993;Hall and Sanes, 1993;Kummer et al., 2006;Salpeter and Loring, 1985;Schaeffer et al., 2001). NMJ formati...

Summary Neuregulins (NRGs) comprise a large family of growth factors that stimulate ERBB receptor tyrosine kinases. NRGs and their receptors ERBBs have been identified as susceptibility genes for diseases such as schizophrenia (SZ) and bipolar disorder. Recent studies have revealed complex Nrg/Erbb signaling networks that regulate the assembly of neural circuitry, myelination, neurotransmission and synaptic plasticity. Evidence indicates there is an optimal level of NRG/ERBB signaling in the brain and deviation from it impairs brain functions. NRGs/ERBBs and downstream signaling pathways may provide therapeutic targets for specific neuropsychiatric symptoms.

Neuregulins (NRGs) and their receptors, the ErbB protein tyrosine kinases, are essential for neuronal development, but their functions in the adult CNS are unknown. We report that ErbB4 is enriched in the postsynaptic density (PSD) and associates with PSD-95. Heterologous expression of PSD-95 enhanced NRG activation of ErbB4 and MAP kinase. Conversely, inhibiting expression of PSD-95 in neurons attenuated NRG-mediated activation of MAP kinase. PSD-95 formed a ternary complex with two molecules of ErbB4, suggesting that PSD-95 facilitates ErbB4 dimerization. Finally, NRG suppressed 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.

Mitochondrial injury, characterized by outer membrane permeabilization and consequent release of apoptogenic factors, is a key to apoptosis of mammalian cells. Bax and Bak, two multidomain Bcl-2 family proteins, provide a requisite gateway to mitochondrial injury. However it is unclear how Bax and Bak cooperate to provoke mitochondrial injury and whether their roles are redundant. Here, we have identified a unique role of Bak in mitochondrial fragmentation, a seemingly morphological event that contributes to mitochondrial injury during apoptosis. We show that mitochondrial fragmentation is attenuated in Bak-deficient mouse embryonic fibroblasts, baby mouse kidney cells, and, importantly, also in primary neurons isolated from brain cortex of Bak-deficient mice. In sharp contrast, Bax deficiency does not prevent mitochondrial fragmentation during apoptosis. Bcl-2 and Bcl-XL inhibit mitochondrial fragmentation, and their inhibitory effects depend on the presence of Bak. Reconstitution of Bak into Bax/Bak doubleknockout cells restores mitochondrial fragmentation, whereas reconstitution of Bax is much less effective. Bak interacts with Mfn1 and Mfn2, two mitochondrial fusion proteins. During apoptosis, Bak dissociates from Mfn2 and enhances the association with Mfn1. Mutation of Bak in the BH3 domain prevents its dissociation from Mfn2 and diminishes its mitochondrial fragmentation activity. This study has uncovered a previously unrecognized function of Bak in the regulation of mitochondrial morphological dynamics during apoptosis. By this function, Bak may collaborate with Bax to permeabilize the outer membrane of mitochondria, unleashing the apoptotic cascade.Bax ͉ mitochondria ͉ Bcl-2 ͉ cytochrome c

The murine dishevelled 2 (Dvl2) gene is an ortholog of theDrosophila segment polarity gene Dishevelled, a member of the highly conserved Wingless/Wnt developmental pathway.Dvl2-deficient mice were produced to determine the role ofDvl2 in mammalian development. Mice containing null mutations inDvl2 present with 50% lethality in both inbred 129S6 and in a hybrid 129S6-NIH Black Swiss background because of severe cardiovascular outflow tract defects, including double outlet right ventricle, transposition of the great arteries and persistent truncus arteriosis. The majority of the surviving Dvl2-/- mice were female, suggesting that penetrance was influenced by sex. Expression of Pitx2 and plexin A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural crest development during outflow tract formation. In addition, ∼90%of Dvl2-/- mice have vertebral and rib malformations that affect the proximal as well as the distal parts of the ribs. These skeletal abnormalities were more pronounced in mice deficient for both Dvl1and Dvl2. Somite differentiation markers used to analyzeDvl2-/- and Dvl1-/-;Dvl2-/-mutant embryos revealed mildly aberrant expression of Uncx4.1, delta 1 and myogenin, suggesting defects in somite segmentation. Finally, 2-3% ofDvl2-/- embryos displayed thoracic spina bifida, while virtually all Dvl1/2 double mutant embryos displayed craniorachishisis, a completely open neural tube from the midbrain to the tail. Thus, Dvl2 is essential for normal cardiac morphogenesis,somite segmentation and neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in some phenotypes.

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.