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Developing Nervous System (developing + nervous_system)
Selected AbstractsEffects of early seizures on later behavior and epileptogenicityDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2004Gregory L. Holmes Abstract Both clinical and laboratory studies demonstrate that seizures early in life can result in permanent behavioral abnormalities and enhance epileptogenicity. Understanding the critical periods of vulnerability of the developing nervous system to seizure-induced changes may provide insights into parallel or divergent processes in the development of autism. In experimental rodent models, the consequences of seizures are dependent on age, etiology, seizure duration, and frequency. Recurring seizures in immature rats result in long-term adverse effects on learning and memory. These behavioral changes are paralleled by changes in brain connectivity, changes in excitatory neurotransmitter receptor distribution, and decreased neurogenesis. These changes occur in the absence of cell loss. Although impaired cognitive function and brain changes have been well-documented following early-onset seizures, the mechanisms of seizure-induced dysfunction remain unclear. MRDD Research Reviews 2004;10:101,105. © 2004 Wiley-Liss, Inc. [source] Neonatal encephalopathy in the term infant: Neuroimaging and inflammatory cytokinesDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2002Audrey Foster-Barber Abstract The interrelationship between inflammation and ischemia is complex and poorly understood in the developing nervous system. In the preterm newborn, maternal infection may predispose to white matter injury and may be associated with cytokine elevation. In the term infant, few studies exist linking elevation of cytokines with encephalopathy and poor neurodevelopmental outcome. This review discusses the interplay among inflammatory cytokines, neonatal encephalopathy, and neuroimaging parameters. MRDD Research Reviews 2002;8:20,24. © 2002 Wiley-Liss, Inc. [source] Differential expression of sphingosine-1-phosphate receptors 1-5 in the developing nervous systemDEVELOPMENTAL DYNAMICS, Issue 2 2009H. Meng Abstract Sphingosine-1-phosphate (S1P) binds to G protein,coupled receptors and can regulate a wide range of cellular functions. In a previous study, we isolated two key enzymes in the S1P pathway that were expressed in migrating neural crest cells. To determine if S1P receptors are present in neural crest cells or peripheral nervous system, we examine the expression patterns of S1P receptors (S1pr1-5) in mouse, and s1pr1 and s1pr3 in chick embryos. Here, we present a comprehensive expression analysis of these receptors using in situ hybridizations, which provide spatiotemporal information. We showed that S1pr2 was expressed in migrating cranial neural crest cells and enteric neurons. S1pr1 was prominently expressed in the neuroepithelium whereas S1pr4 and S1pr5 were in neurons at later stages. On the contrary, S1pr3 was predominantly detected in non-neuronal cells within and surrounding neural structures. We also described novel expression sites for S1P receptors in the developing nervous system. Developmental Dynamics 238:487,500, 2009. © 2009 Wiley-Liss, Inc. [source] SPARC is expressed by macroglia and microglia in the developing and mature nervous systemDEVELOPMENTAL DYNAMICS, Issue 5 2008Adele J. Vincent Abstract SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that is highly expressed during development, tissue remodeling, and repair. SPARC produced by olfactory ensheathing cells (OECs) can promote axon sprouting in vitro and in vivo. Here, we show that in the developing nervous system of the mouse, SPARC is expressed by radial glia, blood vessels, and other pial-derived structures during embryogenesis and postnatal development. The rostral migratory stream contains SPARC that becomes progressively restricted to the SVZ in adulthood. In the adult CNS, SPARC is enriched in specialized radial glial derivatives (Müller and Bergmann glia), microglia, and brainstem astrocytes. The peripheral glia, Schwann cells, and OECs express SPARC throughout development and in maturity, although it appears to be down-regulated with maturation. These data suggest that SPARC may be expressed by glia in a spatiotemporal manner consistent with a role in cell migration, neurogenesis, synaptic plasticity, and angiogenesis. Developmental Dynamics 237:1449-1462, 2008. © 2008 Wiley-Liss, Inc. [source] Rab23 GTPase is expressed asymmetrically in Hensen's node and plays a role in the dorsoventral patterning of the chick neural tubeDEVELOPMENTAL DYNAMICS, Issue 11 2007Naixin Li Abstract The mouse Rab23 protein, a Ras-like GTPase, inhibits signaling through the Sonic hedgehog pathway and thus exerts a role in the dorsoventral patterning of the spinal cord. Rab23 mouse mutant embryos lack dorsal spinal cord cell types. We cloned the chicken Rab23 gene and studied its expression in the developing nervous system. Chick Rab23 mRNA is initially expressed in the entire neural tube but retracts to the dorsal alar plate. Unlike in mouse, we find Rab23 in chick already expressed asymmetrically during gastrulation. Ectopic expression of Rab23 in ventral midbrain induced dorsal genes (Pax3, Pax7) ectopically and reduced ventral genes (Nkx2.2 and Nkx6) without influencing cell proliferation or neurogenesis. Thus, in the developing brain of chick embryos Rab23 acts in the same manner as described for the caudal spinal cord in mouse. These data indicate that Rab23 plays an important role in patterning the dorso-ventral axis by dorsalizing the neural tube. Developmental Dynamics 236:2993,3006, 2007. © 2007 Wiley-Liss, Inc. [source] Neuronal leucine-rich repeat 6 (XlNLRR-6) is required for late lens and retina development in Xenopus laevisDEVELOPMENTAL DYNAMICS, Issue 4 2006Adam D. Wolfe Abstract Leucine-rich repeat proteins expressed in the developing vertebrate nervous system comprise a complex, multifamily group, and little is known of their developmental function in vivo. We have identified a novel member of this group in Xenopus laevis, XlNLRR-6, and through sequence and phylogenetic analysis, have placed it within a defined family of vertebrate neuronal leucine-rich repeat proteins (NLRR). XlNLRR-6 is expressed in the developing nervous system and tissues of the eye beginning at the neural plate stage, and expression continues throughout embryonic and larval development. Using antisense morpholino oligonucleotide (MO) -mediated knockdown of XlNLRR-6, we demonstrate that this protein is critical for development of the lens, retina, and cornea. Reciprocal transplantation of presumptive lens ectoderm between MO-treated and untreated embryos demonstrate that XlNLRR-6 plays autonomous roles in the development of both the lens and retina. These findings represent the first in vivo functional analysis of an NLRR family protein and establish a role for this protein during late differentiation of tissues in the developing eye. Developmental Dynamics 235:1027,1041, 2006. © 2006 Wiley-Liss, Inc. [source] Expression of qBrn-1, a new member of the POU gene family, in the early developing nervous system and embryonic kidneyDEVELOPMENTAL DYNAMICS, Issue 4 2006Lei Lan Abstract It has been shown that POU domain genes play critical roles in the development of the nervous system. We have obtained a new member of the class III POU domain genes, qBrn-1, from the cDNA library of embryonic day 5 quail and have made an extensive expression pattern analysis of qBrn-1 and qBrn-2 throughout the early embryonic development by in situ hybridization. With a specific antibody we prepared, further analysis by immunohistochemistry showed that the location of qBrn-1 protein was consistent with that of the transcripts in the early developing quail. Our results showed that both qBrn-1 and qBrn-2 were preferentially expressed in the developing central nervous system, and their transcripts were initially detected in the neural plate and later in the distinct regions of the neural tube with a stage-dependent pattern. Moreover, their expression was also detected in both notochord and neural crests. However, qBrn-1 signal, different from qBrn-2, was more widely found in the auditory pits, branchial arches, and in the mesodermal components of the developing kidney. And the expression of qBrn-1 in nephric region was earlier and wider than that of mouse Brn-1, suggesting the characteristic function of qBrn-1 in the kidney formation. The distinct dynamic expression patterns of qBrn-1 and qBrn-2 indicate multiple roles of the class III POU genes in quail neurogenesis and organogenesis. Developmental Dynamics 235:1107,1114, 2006. © 2006 Wiley-Liss, Inc. [source] Members of the Plag gene family are expressed in complementary and overlapping regions in the developing murine nervous systemDEVELOPMENTAL DYNAMICS, Issue 3 2005Sharmila Alam Abstract In the developing nervous system, cell fate specification and proliferation are tightly coupled events, ensuring the coordinated generation of the appropriate numbers and correct types of neuronal and glial cells. While it has become clear that tumor suppressor genes and oncogenes are key regulators of cell division in tumor cells, their role in normal cellular and developmental processes is less well understood. Here we present a comparative analysis of the expression profiles of the three members of the pleiomorphic adenoma gene (Plag) family, which encode zinc finger transcription factors previously characterized as tumor suppressors (Zac1) or oncogenes (Plag1, Plag-l2). We focused our analysis on the developing nervous system of mouse where we found that the Plag genes were expressed in both unique and overlapping patterns in the central and peripheral nervous systems, and in olfactory and neuroendocrine lineages. Based on their patterns of expression, we suggest that members of the Plag gene family might control cell fate and proliferation decisions in the developing nervous system and propose that deciphering these functions will help to explain why their inappropriate inactivation/activation leads to tumor formation. Developmental Dynamics 234:772,782, 2005. © 2005 Wiley-Liss, Inc. [source] Cloning and expression of three zebrafish roundabout homologs suggest roles in axon guidance and cell migrationDEVELOPMENTAL DYNAMICS, Issue 2 2001Jeong-Soo Lee Abstract We report the cloning and expression patterns of three novel zebrafish Roundabout homologs. The Roundabout (robo) gene encodes a transmembrane receptor that is essential for axon guidance in Drosophila and Robo family members have been implicated in cell migration. Analysis of extracellular domains and conserved cytoplasmic motifs shows that zebrafish Robo1 and Robo2 are orthologs of mammalian Robo1 and Robo2, respectively, while zebrafish Robo3 is likely to be an ortholog of mouse Rig-1. The three zebrafish robos are expressed in distinct but overlapping patterns during embryogenesis. They are highly expressed in the developing nervous system, including the olfactory system, visual system, hindbrain, cranial ganglia, spinal cord, and posterior lateral line primordium. They are also expressed in several nonneuronal tissues, including somites and fin buds. The timing and patterns of expression suggest roles for zebrafish robos in axon guidance and cell migration. Wiley-Liss, Inc. © 2001 Wiley-Liss, Inc. [source] Zebrafish E-cadherin: Expression during early embryogenesis and regulation during brain developmentDEVELOPMENTAL DYNAMICS, Issue 2 2001Sherry G. Babb Abstract Zebrafish E-cadherin (cdh1) cell adhesion molecule cDNAs were cloned. We investigated spatial and temporal expression of cdh1 during early embryogenesis. Expression was observed in blastomeres, the anterior mesoderm during gastrulation, and developing epithelial structures. In the developing nervous system, cdh1 was detected at the pharyngula stage (24 hpf) in the midbrain-hindbrain boundary (MHB). Developmental regulation of MHB formation involves wnt1 and pax2.1. wnt1 expression preceded cdh1 expression during MHB formation, and cdh1 expression in the MHB was dependent on normal development of this structure. © 2001 Wiley-Liss, Inc. [source] Brain-derived neurotrophic factor and the development of structural neuronal connectivityDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2010Susana Cohen-Cory Abstract During development, neural networks are established in a highly organized manner, which persists throughout life. Neurotrophins play crucial roles in the developing nervous system. Among the neurotrophins, brain-derived neurotrophic factor (BDNF) is highly conserved in gene structure and function during vertebrate evolution, and serves an important role during brain development and in synaptic plasticity. BDNF participates in the formation of appropriate synaptic connections in the brain, and disruptions in this process contribute to disorders of cognitive function. In this review, we first briefly highlight current knowledge on the expression, regulation, and secretion of BDNF. Further, we provide an overview of the possible actions of BDNF in the development of neural circuits, with an emphasis on presynaptic actions of BDNF during the structural development of central neurons. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 2010 [source] Mechanical computation in neuronsDEVELOPMENTAL NEUROBIOLOGY, Issue 11 2009Jummi Laishram Abstract Growth cones are the main motile structures located at the tip of neurites and are composed of a lamellipodium from which thin filopodia emerge. In this article, we analyzed the kinetics and dynamics of growth cones with the aim to understand two major issues: first, the strategy used by filopodia and lamellipodia during their exploration and navigation; second, what kind of mechanical problems neurons need to solve during their operation. In the developing nervous system and in the adult brain, neurons constantly need to solve mechanical problems. Growth cones must decide how to explore the environment and in which direction to grow; they also need to establish the appropriate contacts, to avoid obstacles and to determine how much force to exert. Here, we show that in sparse cultures, filopodia grow and retract following statistical patterns, nearly optimal for an efficient exploration of the environment. In a dense culture, filopodia exploration is still present although significantly reduced. Analysis on 1271, 6432, and 185 pairs of filopodia of DRG, PC12 and Hippocampal neurons respectively showed that the correlation coefficient |,| of the growth of more than 50% of filopodia pairs was >0.15. From a computational point of view, filopodia and lamellipodia motion can be described by a random process in which errors are corrected by efficient feedback loops. This article argues that neurons not only process sensory signals, but also solve mechanical problems throughout their entire lifespan, from the early stages of embryogenesis to adulthood. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source] Overview of retinoid metabolism and functionDEVELOPMENTAL NEUROBIOLOGY, Issue 7 2006Rune Blomhoff Abstract Retinoids (vitamin A) are crucial for most forms of life. In chordates, they have important roles in the developing nervous system and notochord and many other embryonic structures, as well as in maintenance of epithelial surfaces, immune competence, and reproduction. The ability of all- trans retinoic acid to regulate expression of several hundred genes through binding to nuclear transcription factors is believed to mediate most of these functions. The role of all- trans retinoic may extend beyond the regulation of gene transcription because a large number of noncoding RNAs also are regulated by retinoic acid. Additionally, extra-nuclear mechanisms of action of retinoids are also being identified. In organisms ranging from prokaryotes to humans, retinal is covalently linked to G protein-coupled transmembrane receptors called opsins. These receptors function as light-driven ion pumps, mediators of phototaxis, or photosensory pigments. In vertebrates phototransduction is initiated by a photochemical reaction where opsin-bound 11- cis -retinal is isomerized to all- trans -retinal. The photosensitive receptor is restored via the retinoid visual cycle. Multiple genes encoding components of this cycle have been identified and linked to many human retinal diseases. Central aspects of vitamin A absorption, enzymatic oxidation of all- trans retinol to all- trans retinal and all- trans retinoic acid, and esterification of all- trans retinol have been clarified. Furthermore, specific binding proteins are involved in several of these enzymatic processes as well as in delivery of all- trans retinoic acid to nuclear receptors. Thus, substantial progress has been made in our understanding of retinoid metabolism and function. This insight has improved our view of retinoids as critical molecules in vision, normal embryonic development, and in control of cellular growth, differentiation, and death throughout life. © 2006 Wiley Periodicals, Inc. J Neurobiol 66: 606,630, 2006 [source] GABAB receptor expression and function in olfactory receptor neuron axon growthDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2004Catherine A. Priest Abstract Neurotransmitters have been implicated in regulating growth cone motility and guidance in the developing nervous system. Anatomical and electrophysiological studies show the presence of functional GABAB receptors on adult olfactory receptor neuron (ORN) nerve terminals. Using antisera against the GABAB R1a/b receptor isoforms we show that developing mouse olfactory receptor neurons express GABAB receptors from embryonic day 14 through to adulthood. GABAB receptors are present on axon growth cones from both dissociated ORNs and olfactory epithelial explants. Neurons in the olfactory bulb begin to express glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA, from E16 through to adulthood. When dissociated ORNs were cultured in the presence of the GABAB receptor agonists, baclofen or SKF97541, neurite outgrowth was significantly reduced. Concurrent treatment of the neurons with baclofen and the GABAB receptor antagonist CGP54626 prevented the inhibitory effects of baclofen on ORN neurite outgrowth. These results show that growing ORN axons express GABAB receptors and are sensitive to the effects of GABAB receptor activation. Thus, ORNs in vivo may detect GABA release from juxtaglomerular cells as they enter the glomerular layer and use this as a signal to limit their outgrowth and find synaptic targets in regeneration and development. © 2004 Wiley Periodicals, Inc. J Neurobiol 60:154,165, 2004 [source] Diazepam Terminates Brief but Not Prolonged Seizures in Young, Naďve RatsEPILEPSIA, Issue 8 2003Howard P. Goodkin Summary: Purpose: Ample evidence exists from both clinical and animal studies that the success of benzodiazepine intervention during status epilepticus (SE) in the mature nervous system is inversely related to seizure duration. This relationship has not been well studied in the developing nervous system. Methods: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium-pilocarpine model of secondarily generalized seizure in the rat by using naďve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60). Results: In all age groups, the dosage of DZP that stopped the seizures at 5 min was not effective in terminating seizures at 60 min. This decline in efficacy was present as early as 15 min after seizure onset. Conclusions: These findings demonstrate that the inverse relation between the success of benzodiazepine intervention and seizure duration is observed in young as well as in adult rats and provide further evidence that intervention for SE should commence early. [source] Switching of the transmitters that mediate hindbrain correlated activity in the chick embryoEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2009Hiraku Mochida Abstract Widely propagating correlated neuronal activity is a hallmark of the developing nervous system. The activity is usually mediated by multiple transmitters, and the contribution of gap junctions has also been suggested in several systems. In some structures, such as the retina and spinal cord, it has been shown that the dominant transmitter mediating the correlated wave switches from acetylcholine to glutamate during development, although the functional significance of this phenomenon has not been clarified. An important question is whether such a transmitter switch occurs in other systems, especially in the brain. In the present study, we demonstrate that the major transmitter mediating correlated wave activity in the embryonic chick hindbrain changes from acetylcholine/,-aminobutyric acid (GABA)/glycine to glutamate/GABA as development proceeds. The results show for the first time that the dominant transmitter switches from acetylcholine to glutamate in a region other than the retina and spinal cord. This finding sheds more light on the role of nicotinic acetylcholine receptors in the generation of correlated wave activity, which is considered to regulate the development of the nervous system. [source] Chronic interleukin-6 alters the level of synaptic proteins in hippocampus in culture and in vivoEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Elly J. F. Vereyken Abstract There is now considerable evidence that the level of expression of the proinflammatory cytokine, interleukin-6 (IL-6), is increased in the central nervous system (CNS) during neuroinflammatory conditions such as occurs in neurological disorders and in disease and injury. However, our understanding of the consequences of increased expression of IL-6 on the CNS is still limited, especially with respect to the developing nervous system, which is known to be particularly vulnerable to environmental factors. To address this issue, we investigated the properties of cultured hippocampal neurons exposed chronically to IL-6 during the main period of morphological and physiological development, which occurs during the first 2 weeks of culture. IL-6 was tested at 500 U/mL, considered to reflect a pathophysiologic concentration. The morphological features of neuronal development in the control and IL-6-treated cultures appeared similar. However, Western blot analysis showed a significant reduction in the level of Group-II metabotropic receptors (mGluR2/3) and L-type Ca2+ channels in the IL-6-treated cultures. A similar reduction in mGluR2/3 and L-type Ca2+ channel protein was observed in transgenic mice that over-express IL-6 in the CNS through astrocyte production starting early in development. Analysis of Ca2+ signals produced by spontaneous synaptic network activity in the hippocampal cultures and effects of a mGluR2/3 agonist and antagonist showed that the reduced levels of mGluR2/3 impact on the functional properties of hippocampal synaptic network activity. These results have important implications relative to the mechanisms responsible for altered CNS function during conditions associated with increased levels of IL-6 in the CNS. [source] Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2003Annalisa Bolis Abstract Rac3 is one of the three known Rac GTPases in vertebrates. Rac3 shows high sequence homology to Rac1, and its transcript is specifically expressed in the developing nervous system, where its localization and function are unknown. By using Rac3-specific antibodies, we show that the endogenous Rac3 protein is differentially expressed during mouse brain development, with a peak of expression at times of neuronal maturation and synaptogenesis. Comparison with Rac1 shows clear-cut differences in the overall distribution of the two GTPases in the developing brain, and in their subcellular distribution in regions of the brain where both proteins are expressed. At P7, Rac3 staining is particularly marked in the deep cerebellar nuclei and in the pons, where it shows a discontinuous distribution around the neuronal cell bodies, in contrast with the diffuse staining of Rac1. Rac3 does not evidently co-localize with pre- and post-synaptic markers, nor with GFAP-positive astrocytes, but it clearly co-localizes with actin filaments, and with the terminal portions of calbindin-positive Purkinje cell axons in the deep cerebellar nuclei. Our data implicate Rac3 in neuronal differentiation, and support a specific role of this GTPase in actin-mediated remodelling of Purkinje cell neuritic terminals at time of synaptogenesis. [source] Developmental roles for Homer: more than just a pretty scaffoldJOURNAL OF NEUROCHEMISTRY, Issue 1 2009Lisa Foa Abstract Homer proteins are best known as scaffold proteins at the post-synaptic density where they facilitate synaptic signalling and are thought to be required for learning and memory. Evidence implicating Homer proteins in the development of the nervous system is also steadily accumulating. Homer is highly conserved and is expressed at key developmental time points in the nervous system of several species. Homer regulates intracellular calcium homeostasis, clustering and trafficking of receptors and proteins at the cytosolic surface of the plasma membrane, transcription and translation, and cytoskeletal organization. Each of these functions has obvious potential to regulate neuronal development, and indeed Homer is implicated in several pathologies associated with the developing nervous system. Current data justify more critical experimental approaches to the role of Homer in the developing nervous system and related neurological disorders. [source] BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulationJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Yinghui Hu Abstract It is clear that brain-derived neurotrophic factor (BDNF) plays a crucial role in organizing the response of the genome to dynamic changes in the extracellular environment that enable brain plasticity. BDNF has emerged as one of the most important signaling molecules for the developing nervous system as well as the impaired nervous system, and multiple diseases, such as Alzheimer's, Parkinson's, Huntington's, epilepsy, Rett's syndrome, and psychiatric depression, are linked by their association with potential dysregulation of BDNF-driven signal transduction programs. These programs are responsible for controlling the amount of activated transcription factors, such as cAMP response element binding protein, that coordinate the expression of multiple brain proteins, like ion channels and early growth response factors, whose job is to maintain the balance of excitation and inhibition in the nervous system. In this review, we will explore the evidence for BDNF's role in gene regulation side by side with its potential role in the etiology of neurological diseases. It is hoped that by bringing the datasets together in these diverse fields we can help develop the foundation for future studies aimed at understanding basic principles of gene regulation in the nervous system and how they can be harnessed to develop new therapeutic opportunities. [source] Lifeguard/neuronal membrane protein 35 regulates Fas ligand-mediated apoptosis in neurons via microdomain recruitmentJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Miriam Fernández Abstract Fas ligand (FasL)-receptor system plays an essential role in regulating cell death in the developing nervous system, and it has been implicated in neurodegenerative and inflammatory responses in the CNS. Lifeguard (LFG) is a protein highly expressed in the hippocampus and the cerebellum, and it shows a particularly interesting regulation by being up-regulated during postnatal development and in the adult. We show that over-expression of LFG protected cortical neurons from FasL-induced apoptosis and decreased caspase-activation. Reduction of endogenous LFG expression by small interfering RNA sensitized cerebellar granular neurons to FasL-induced cell death and caspase-8 activation, and also increased sensitivity of cortical neurons. In differentiated cerebellar granular neurons, protection from FasL-induced cell death could be attributed exclusively to LFG and appears to be independent of FLICE inhibitor protein. Thus, LFG is an endogenous inhibitor of FasL-mediated neuronal death and it mediates the FasL resistance of CNS differentiated neurons. Finally, we also demonstrate that LFG is detected in lipid rafts microdomains, where it may interact with Fas receptor and regulate FasL-activated signaling pathways. [source] Netrin induces down-regulation of its receptor, Deleted in Colorectal Cancer, through the ubiquitin,proteasome pathway in the embryonic cortical neuronJOURNAL OF NEUROCHEMISTRY, Issue 1 2005Tae-Hong Kim Abstract The proper regulation of temporal and spatial expression of the axon guidance cues and their receptors is critical for the normal wiring of nervous system during development. Netrins, a family of secreted guidance cues, are involved in the midline crossing of spinal commissural axons and in the guidance of cortical efferents. Axons normally lose the responsiveness to their attractants when they arrive at their targets, where the attractant is produced. However the molecular mechanism is still unknown. We investigated the molecular mechanism of down-regulation of netrin-1 signaling in the embryonic cortical neurons. Netrin-1 induced the ubiquitination and proteolytic cleavage of Deleted in Colorectal Cancer (DCC), a transmembrane receptor for netrin, in dissociated cortical neurons. A dramatic decrease of DCC level particularly on the cell surface was also observed after netrin-1 stimulation. Specific ubiquitin,proteasome inhibitors prevented the netrin-induced DCC cleavage and decrease of cell surface DCC. We suggest that the ligand-mediated down-regulation of DCC might participate in the loss of netrin-responsiveness in the developing nervous system. [source] Carbohydrate,protein interactions between HNK-1-reactive sulfoglucuronyl glycolipids and the proteoglycan lectin domain mediate neuronal cell adhesion and neurite outgrowthJOURNAL OF NEUROCHEMISTRY, Issue 2 2001Ryu Miura Lecticans, a family of chondroitin sulfate proteoglycans, represent the largest group of proteoglycans expressed in the nervous system. We previously showed that the C-type lectin domains of lecticans bind two classes of sulfated cell surface glycolipids, sulfatides and HNK-1-reactive sulfoglucuronylglycolipids (SGGLs). In this paper, we demonstrate that the interaction between the lectin domain of brevican, a nervous system-specific lectican, and cell surface SGGLs acts as a novel cell recognition system that promotes neuronal adhesion and neurite outgrowth. The Ig chimera of the brevican lectin domain bind to the surface of SGGL-expressing rat hippocampal neurons. The substrate of the brevican chimera promotes adhesion and neurite outgrowth of hippocampal neurons. The authentic, full-length brevican also promotes neuronal cell adhesion and neurite outgrowth. These activities of brevican substrates are neutralized by preincubation of cells with HNK-1 monoclonal antibodies and by pretreatment of the brevican substrates with purified SGGLs. Brevican and HNK-1 carbohydrates are coexpressed in specific layers of the developing hippocampus where axons from entorhinal neurons elongate. Our observations suggest that cell surface SGGLs and extracellular lecticans comprise a novel cell-substrate recognition system operating in the developing nervous system. [source] Heregulin upregulates the expression of nitric oxide synthase (NOS)-1 in rat cerebellar granule neurons via the ErbB4 receptorJOURNAL OF NEUROCHEMISTRY, Issue 1 2001Randy Krainock Heregulin plays key roles in regulating cell number, determining fate and establishing pattern in the developing nervous system via specific receptors (ErbBs), including ErbB4. Two recent reports have shown that ErbB4 forms a complex with postsynaptic density proteins, which are, in turn, known to complex with nitric oxide synthase (NOS)-1. To reveal whether heregulin might regulate the expression of NOS-1, cultures enriched in cerebellar granule cells were exposed to heregulin for 72 h. This treatment resulted in an increase in NOS-1 protein (> 70%), an effect mediated by the ErbB4 receptor. While nitric oxide might mediate some of the downstream effects of heregulin in the nervous system, heregulin treatment neither enhanced granule cell survival, nor protected neurons from acute glutamate excitotoxicity. [source] Peptides derived from the solvent-exposed loops 3 and 4 of BDNF bind TrkB and p75NTR receptors and stimulate neurite outgrowth and survivalJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2010Kristina Fobian Abstract Brain-derived neurotrophic factor (BDNF) is critically involved in modeling the developing nervous system and is an important regulator of a variety of crucial functions in the mature CNS. BDNF exerts its action through interactions with two transmembrane receptors, either separately or in concert. BDNF has been implicated in several neurological disorders, and irregularities in BDNF function may have severe consequences. Administration of BDNF as a drug has thus far yielded few practicable results, and the potential side effects when using a multifunctional protein are substantial. In an effort to produce more specific compounds without side effects, small peptides mimicking protein function have been developed. The present study characterized two mimetic peptides, Betrofin 3 and Betrofin 4, derived from the BDNF sequence. Both Betrofins bound the cognate BDNF receptors, TrkB and p75NTR, and induced neurite outgrowth and enhanced neuronal survival, probably by inducing signaling through tha Akt and MAPK pathways. Distinct, charged residues within the Betrofin sequences were identified as important for generating the neuritogenic response, which was also inhibited when BDNF was added together with either Betrofin, indicating partial agonistic effects of the peptides. Thus, two peptides derived from BDNF induced neurite outgrowth and enhanced neuronal survival, probably through binding to BDNF receptors. © 2009 Wiley-Liss, Inc. [source] The Role of Neurotrophic Factors, Apoptosis-Related Proteins, and Endogenous Antioxidants in the Differential Temporal Vulnerability of Neonatal Cerebellum to EthanolALCOHOLISM, Issue 4 2003Marieta Barrow Heaton Background: Ethanol produces abnormalities in the developing nervous system, with certain regions being vulnerable during well-defined periods. Neonatal rodent cerebellum is particularly susceptible to ethanol during the early postnatal period [on postnatal days 4-5 (P4-5)], while this region is resistant to ethanol at a slightly later time (P7-9). We assessed basal levels of several substances which may be involved in differential temporal ethanol vulnerability in neonatal cerebellum, and analyzed alterations in these substances after early ethanol exposure. Methods: Assessments were made of neurotrophic factors nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4; apoptosis-related proteins Bcl-2, Bcl-xl, Bax, Bcl-xs, Bad, phosphorylated-Bad, phosphorylated-Akt, and phosphorylated-c-Jun N-terminal kinase; and the antioxidants superoxide dismutase, glutathione reductase, and catalase. These analyses quantified basal levels (in controls), and sequential changes following acute ethanol exposure at the vulnerable and resistant cerebellar periods (P4, P7). Results: Comparisons of basal levels of the molecules assessed between P4 and P7 revealed higher levels of total proapoptotic Bad at p4, higher levels of the protective pAkt kinase at P7, and lower levels of proapoptotic pJNK at P7. Other basal levels did not differ. While ethanol-mediated alterations were found at both ages favoring both apoptosis and survival, the apoptosis-promoting changes produced on P4 exceeded those on P7, and most occurred within the first 2 hr after exposure, a critical survival/death period. The number of alterations favoring survival were similar at the two ages, but at P7 most occurred within the first 2 hr after exposure, possibly acting in a protective manner. Conclusions: Differential temporal vulnerability to ethanol in the neonatal cerebellum appears to be paralleled by cellular alterations in neurotrophic factors, apoptosis-regulatory proteins, and/or antioxidant activities which generally favor apoptosis at the most sensitive age and survival at the resistant age. [source] Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous systemNEUROPATHOLOGY, Issue 3 2002Payam Rezaie Periventricular leukomalacia (PVL) occurring in premature infants, represents a major precursor for neurological and intellectual impairment, and cerebral palsy in later life. The disorder is characterized by multifocal areas of necrosis found deep in the cortical white matter, which are often symmetrical and occur adjacent to the lateral ventricles. There is no known cure for PVL. Factors predisposing to PVL include birth trauma, asphyxia and respiratory failure, cardiopulmonary defects, premature birth/low birthweight, associated immature cerebrovascular development and lack of appropriate autoregulation of cerebral blood flow in response to hypoxic-ischemic insults. The intrinsic vulnerability of oligodendrocyte precursors is considered as central to the pathogenesis of PVL. These cells are susceptible to a variety of injurious stimuli including free radicals and excitotoxicity induced by hypoxic-ischemic injury (resulting from cerebral hypoperfusion), lack of trophic stimuli, as well as secondary associated events involving microglial and astrocytic activation and the release of pro-inflammatory cytokines TNF-, and IL-6. It is yet unclear whether activated astrocytes and microglia act as principal participants in the development of PVL lesions, or whether they are representatives of an incidental pathological response directed towards repair of tissue injury in PVL. Nevertheless, the accumulated evidence points to a pathological contribution of microglia towards damage. The topography of lesions in PVL most likely reflects a combination of the relatively immature cerebrovasculature together with a failure in perfusion and/or hypoxia during the greatest period of vulnerability occurring around mid-to-late gestation. Mechanisms underlying the pathogenesis of PVL have so far been related to prenatal ischemic injury to the brain initiated within the third trimester, which result in global cognitive and developmental delay and motor disturbances. Over the past few years, several epidemiological and experimental studies have implicated intrauterine infection and chorioamnionitis as causative in the pathogenesis of PVL. In particular, recent investigations have shown that inflammatory responses in the fetus and neonate can contribute towards neonatal brain injury and development-related disabilities including cerebral palsy. This review presents current concepts on the pathogenesis of PVL and emphasizes the increasing evidence for an inflammatory pathogenic component to this disorder, either resulting from hypoxic-ischemic injury or from infection. These findings provide the basis for clinical approaches targeted at protecting the premature brain from inflammatory damage, which may prove beneficial for treating PVL, if identified early in pathogenesis. [source] Vascular endothelial growth factor and the nervous systemNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2004A. Brockington Vascular endothelial growth factor (VEGF) is an angiogenic factor essential for the formation of new blood vessels during embryogenesis and in many pathological conditions. A new role for VEGF as a neurotrophic factor has recently emerged. In the developing nervous system, VEGF plays a pivotal role not only in vascularization, but also in neuronal proliferation, and the growth of coordinated vascular and neuronal networks. After injury to the nervous system, activation of VEGF and its receptors may restore blood supply and promote neuronal survival and repair. There is a growing body of evidence that VEGF is essential for motor neurone survival, and that aberrant regulation of VEGF may play a role in the degeneration of neurones in diseases such as amyotrophic lateral sclerosis. [source] Microglial colonization of the developing mouse brain: the effect of CD11b deletionNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2002J. K. Jeetle Introduction:, Microglia are resident mononuclear phagocytes of the central nervous system, which colonize the brain both prenatally and after birth. It is proposed that they enter the brain initially via the surrounding mesenchyme, via ventricles and later through blood vessels, but the mechanisms of entry and signals used for migration are still to be established. Previous studies have shown that ligands for some integrin adhesion molecules expressed on blood vessels in the developing nervous system (particularly ICAM-1 and ICAM-2 which bind CD11a/LFA-1 and CD11b/Mac-1), may act as potential recruiting signals for microglial precursors. This study addressed whether CD11b is influential on the migration of microglial precursors into the developing CNS. Material and methods:,Ricinus communis agglutinin-1 (RCA-1) lectin histochemistry was employed to anatomically map the distribution of amoeboid and ramified microglia from embryonic day 15 (E15) to birth. Embryonic mouse brains from CD11b knockout (,/,) (n = 42), and heterozygote (+/,) (n = 52) mice generated on a C57/BL6 background (Melo et al. Cell Immunol 2000; 205: 13,23) and wild-type (+/+) (n = 37) litter mates were fixed in Bouin's solution, processed to paraffin wax and serially sectioned at 15,40 µm. To investigate further potential signals for recruiting microglial precursors, brains were immunochemically screened for integrins CD11a, CD11b, CD18, ,X, VLA-4 and the chemokine MCP-1. Results:, Microscopic analysis revealed the morphological transition of microglia from predominantly amoeboid forms at E15,E16 to a flourishing population of ramified cells at E19,E20. RCA-1 histochemistry showed no clear differences in microglial distribution or timing of colonization between CD11b (,/,) and wild-type mice from E15 to birth. Although CD11b deletion did not influence the timing of microglial ramification, there appeared to be fewer ramified cells in (,/,) mice within comparative brain regions. This requires further quantitative morphometric analysis. Of the integrins investigated, none were restricted to microglia and only VLA-4 and ,X showed reactivity within the CNS. However, MCP-1 was notably localized to the cortical plate within all genotypes, consistent with previous findings in human foetal CNS (Rezaie & Male. Microsc Res Tech 1999; 45: 359,382). Conclusion:, The results suggest that CD11b has little influence on the timing or regional distribution of microglia in the developing murine CNS. It is more likely that CD11b is only one of several factors that influence the migration and differentiation of these cells. [source] | |||||||||||||