Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

Schizophrenia is a highly debilitating mental disorder that affects approximately 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.     

Neuregulin 1 and susceptibility to schizophrenia

The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.     

Sex, hormones and affective arousal circuitry dysfunction in schizophrenia

Women with schizophrenia express affective disturbances disproportionately more than men. Brain regions implicated in the affective arousal circuitry also regulate the hypothalamic-pituitary-adrenal and -gonadal systems, which are dysfunctional in schizophrenia. This review will argue that understanding the etiology of affective arousal deficits in schizophrenia is intimately connected with characterizing the role of neuroendocrine dysfunction and sex effects in schizophrenia. Further, the etiology of these neuroendocrine deficits begins during fetal development, during a period of time that coincides with the sexual differentiation of the brain and the vulnerability for schizophrenia. Studying the links between deficits in neuroendocrine systems and the affective arousal system in schizophrenia will provide clues to understanding the development of sex differences in schizophrenia and thereby its etiology.     

Neuregulin signaling on glucose transport in muscle cells

Neuregulin-1, a growth factor that potentiates myogenesis induces glucose transport through translocation of glucose transporters, in an additive manner to insulin, in muscle cells. In this study, we examined the signaling pathway required for a recombinant active neuregulin-1 isoform (rhHeregulin-beta(1), 177-244, HRG) to stimulate glucose uptake in L6E9 myotubes. The stimulatory effect of HRG required binding to ErbB3 in L6E9 myotubes. PI3K activity is required for HRG action in both muscle cells and tissue. In L6E9 myotubes, HRG stimulated PKBalpha, PKBgamma, and PKCzeta activities. TPCK, an inhibitor of PDK1, abolished both HRG- and insulin-induced glucose transport. To assess whether PKB was necessary for the effects of HRG on glucose uptake, cells were infected with adenoviruses encoding dominant negative mutants of PKBalpha. Dominant negative PKB reduced PKB activity and insulin-stimulated glucose transport but not HRG-induced glucose transport. In contrast, transduction of L6E9 myotubes with adenoviruses encoding a dominant negative kinase-inactive PKCzeta abolished both HRG- and insulin-stimulated glucose uptake. In soleus muscle, HRG induced PKCzeta, but not PKB phosphorylation. HRG also stimulated the activity of p70S6K, p38MAPK, and p42/p44MAPK and inhibition of p42/p44MAPK partially repressed HRG action on glucose uptake. HRG did not affect AMPKalpha(1) or AMPKalpha(2) activities. In all, HRG stimulated glucose transport in muscle cells by activation of a pathway that requires PI3K, PDK1, and PKCzeta, but not PKB, and that shows cross-talk with the MAPK pathway. The PI3K, PDK1, and PKCzeta pathway can be considered as an alternative mechanism, independent of insulin, to induce glucose uptake.     

The Reelin signaling pathway in mouse cortical development

Most of the cerebral cortex derives from the cortical plate which, in all mammals, is radially organized and develops from inside to outside. Several genes involved in the organization and inside-outside development of the embryonic cortical plate in the mouse form the so-called Reelin signaling pathway. Biochemical and genetic arguments show that the extracellular matrix protein Reelin binds to two lipoprotein receptors (VLDLR and ApoER2), which relay the Reelin signal inside target neurons by docking the tyrosine kinase adapter disabled-1 (Dab1). In addition, biochemical evidence suggests that the integrins alpha 3/beta 1 and protocadherins of the CNR family may also modulate the Reelin signal. The mechanisms by which the presence of Reelin stops migration and instructs the radial organization of cortical plate cells remains unknown.     

Colour vision: cortical circuitry for appearance

Directly stimulating certain cortical neurons can produce a color sensation; a case is reported in which the color perceived by stimulation is the same as the color that most effectively excites the cortical circuitry.     

Neuregulin and ErbB receptor signaling pathways in the nervous system

The neuregulins are a complex family of factors that perform many functions during neural development. Recent experiments have shown that neuregulins promote neuronal migration and differentiation, and regulate the selective expression of neurotransmitter receptors in neurons and at the neuromuscular junction. They also regulate glial commitment, proliferation, survival and differentiation. At interneuronal synapses, neuregulin ErbB receptors associate with PDZ-domain proteins at postsynaptic densities where they can modulate synaptic plasticity. How this combinatorial network - comprising many neuregulin ligands that signal through distinct combinations of dimeric ErbB receptors - elicits its multitude of biological effects is beginning to be resolved.     

Neuregulin1 signaling promotes dendritic spine growth through kalirin

The biological functions of the neuregulin 1 (NRG1) and ERBB4 genes have received much recent attention due to several studies showing associations between these genes and schizophrenia. Moreover, reduced forebrain dendritic spine density is a consistent feature of schizophrenia. It is thus important to understand the mechanisms whereby NRG1 and erbB4 modulate spine morphogenesis. Here, we show that long‐term incubation with NRG1 increases both spine size and density in cortical pyramidal neurons. NRG1 also enhances the content of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptors in spines. Knockdown of ERBB4 expression prevented the effects of NRG1 on spine size, but not on spine density. The effects of NRG1 and erbB4 on spines were mediated by the RacGEF kalirin, a well‐characterized regulator of dendritic spines. Finally, we show that environmental enrichment, known to promote spine growth, robustly enhances the levels of erbB4 protein in the forebrain. These findings provide a mechanistic link between NRG1 signaling and spine morphogenesis.

     

Neuregulin signaling via ErbB receptor assemblies in the nervous system

Neuregulins (NRG) play important roles in the development, maintenance, and repair of the nervous system, with influences on neuronal migration, synaptogenesis, receptor subunit composition, and the proliferation/survival of oligodendrocytes and Schwann cells. However, the precise detail of how the NRGs signal through ErbB receptors, particularly at central synapses, is incomplete. The receptor kinase domain provides sites for association with adaptor proteins. In addition, evidence from recent reports suggests that ErbB2/4 receptors, through their C-terminal amino acids, can form specific associations with scaffolding proteins. The existence of such assemblies expands the range of signaling cascades available to the NRGs.     

Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development

Increasing evidence indicates that development of embryonic central nervous system precursors is tightly regulated by extrinsic cues located in the local environment. Here, we asked whether neurotrophin-mediated signaling through Trk tyrosine kinase receptors is important for embryonic cortical precursor cell development. These studies demonstrate that inhibition of TrkB (Ntrk2) and/or TrkC (Ntrk3) signaling using dominant-negative Trk receptors, or genetic knockdown of TrkB using shRNA, caused a decrease in embryonic precursor cell proliferation both in culture and in vivo. Inhibition of TrkB/C also caused a delay in the generation of neurons, but not astrocytes, and ultimately perturbed the postnatal localization of cortical neurons in vivo. Conversely, overexpression of BDNF in cortical precursors in vivo promoted proliferation and enhanced neurogenesis. Together, these results indicate that neurotrophin-mediated Trk signaling plays an essential, cell-autonomous role in regulating the proliferation and differentiation of embryonic cortical precursors and thus controls cortical development at earlier stages than previously thought.     

A rat model for neural circuitry abnormalities in schizophrenia

Animal models for complex brain disorders, such as schizophrenia, are essential for the interpretation of postmortem findings. These models allow empirical testing of hypotheses regarding the role of genetic and environmental factors, the pathophysiological mechanisms and brain circuits that are responsible for specific neural abnormalities and their associated behavioral impairment, and the effectiveness of therapeutic treatments relative to these diseases. Recently, we developed a rodent model for neural circuitry abnormalities in discrete corticolimbic subregions of subjects with major psychoses. According to our protocol, the GABA-A receptor antagonist picrotoxin is stereotaxically infused in the basolateral amygdala to mimic a GABA defect in this region that is postulated to occur in these disorders. This protocol has been tested with a number of acute and chronic time schedules. Following picrotoxin administration in the basolateral amygdala, changes in GABAergic neurons and/or terminals in hippocampal regions CA2/3 are observed, similar to those seen in major psychoses, as well as a marked reduction in GABA-receptor-mediated currents in pyramidal neurons of this region. This has established the construct and predictive validity of this model for studying limbic-lobe circuitry abnormalities. We propose that this modeling strategy may provide a valid alternative to isomorphic models of these diseases.     

Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment

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Perisomatic inhibition and cortical circuit dysfunction in schizophrenia

Deficits of cognitive control in schizophrenia are associated with altered gamma oscillations in the prefrontal cortex. Paralbumin basket interneurons, which innervate the perisomatic region of pyramidal neurons, appear to play a key role in generating cortical gamma oscillations. In the prefrontal cortex of subjects with schizophrenia, alterations are present in both pre- and post-synaptic markers of the strength of GABA inputs from parvalbumin basket neurons to pyramidal neurons. These alterations may contribute to the neural substrate for impaired gamma oscillations in schizophrenia.     

胰岛素信号转导、昆虫发育与老化

胰岛素及其信号转导的探讨为当代生物学一大热点,研究显示:从线虫到果蝇、小鼠及其人类其胰岛素信号转导路径十分类似。昆虫胰岛素的研究开始于家蚕,在20世纪80年代,日本学者在分离家蚕促前胸腺激素(prothoracictropic hormone,简称PTTH)时,发现所纯化的为一称为家蚕素的神经激素,该激素之氨基酸排列顺序与高等动物体内的胰岛素部分相似,但是家蚕素的生理功能至今仍不是很清楚。而果蝇的分子遗传学研究则显示,胰岛素及其信号转导调控果蝇的生长、发育、寿命等许许多多的生理现象。专一性地改变果蝇前胸腺之胰岛素信号转导,会严重影响幼虫的蜕皮与变态。而作者利用家蚕所进行的研究更显示,将牛的胰岛素注射于家蚕幼虫体内可显着提高其蜕皮激素的分泌,离体培养前胸腺时加入牛胰岛素也可直接增加其激素的分泌,牛胰岛素可直接活化家蚕前胸腺细胞之胰岛素受体及信号分子Akt的磷酸化。另外,从线虫、果蝇到小鼠胰岛素及其信号转导突变体的研究结果显示了胰岛素信号转导调控寿命的重要性。利用猴子及人所进行的研究结果显示,低卡路里摄取之所以会延长寿命是因为卡路里的摄取与胰岛素信号转导的变化有关。因此,不同物种利用相同的胰岛素信号转导通路调控发育及老化机制,该发现大大鼓舞了科学家们利用低等的生物来研究复杂的生命现象。     

Rewiring cell signaling: the logic and plasticity of eukaryotic protein circuitry

Living cells rival computers in their ability to process external information and make complex behavioral decisions. Many of these decisions are made by networks of interacting signaling proteins. Ongoing structural, biochemical and cell-based studies have begun to reveal several common principles by which protein components are used to specifically transmit and process information. Recent engineering studies demonstrate that these relatively simple principles can be used to rewire signaling behavior in a process that mimics the evolution of new phenotypic responses.     

Phospholipid and eicosanoid signaling disturbances in schizophrenia

A variety of biochemical, clinical and genetic evidence suggests that phospholipid metabolism may play an aetiological role in schizophrenia. A key piece of evidence is the reduced vasodilatory response of patients with schizophrenia to nicotinic acid (NA). NA causes vasodilation via the activation of phospholipase A2 (PLA2) leading to the release of free fatty acids from membrane phospholipids and the subsequent production of prostaglandins. Insensitivity to NA may be due to a 'block' in the downstream signaling pathway used by the drug to evoke its response. It can be argued that if such an abnormality occurs in neurons, impaired PLA2-dependent signaling could result in altered glutamateric and dopaminergic transmission in such a way as to produce or exacerbate psychotic symptoms. The complimentary finding of increased PLA2 activity in schizophrenia may be an attempt to overcome the signaling block. It is suggested that intervention aimed at increasing the activity of PLA2-dependent signaling systems may be therapeutically useful in the treatment of the illness.     

Membranes,trafficking, and signaling during animal development

Molecular genetics has been key in allowing developmental biologists to uncover many of the molecules that participate in pattern formation. Cell biology is now beginning to help developmental biologists in their quest to understand how these molecules interact within cells to direct tissue behavior. This is particularly true in the areas of membrane trafficking and cell motility. Recent work has shown that various trafficking events such as secretion, endocytosis, segregation in membrane microdomains, intracellular transport, and targeting to lysosomes regulate various signaling pathways. It is likely that within the context of an embryo, these trafficking events are integrated such that secreted factors reliably orchestrate many developmental decisions.