Differential signaling of the chemokine receptor CXCR4 by stromal-cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes

ArticleinEuropean Journal of Neuroscience 12(1):117 - 125 · December 1999with12 Reads
Impact Factor: 3.18 · DOI: 10.1046/j.1460-9568.2000.00894.x

CXCR4 is the Gi protein-linked seven-transmembrane receptor for the alpha chemokine stromal cell-derived factor 1 (SDF-1), a chemoattractant for lymphocytes. This receptor is highly conserved between human and rodent. CXCR4 is also a coreceptor for entry of human immunodeficiency virus (HIV) in T cells and is expressed in the CNS. To investigate how these CXCR4 ligands influence CNS development and/or function, we have examined the expression and signalling of this chemokine receptor in rat neurons and astrocytes in vitro. CXCR4 transcripts and protein are synthesized by both cell types and in E15 brain neuronal progenitors. In these progenitors, SDF-1, but not gp120 (the HIV glycoprotein), induced activation of extracellular signal regulated kinases (ERKs) 1/2 and a dose-dependent chemotactic response. This chemotaxis was inhibited by Pertussis toxin, which uncouples Gi proteins and the bicyclam AMD3100, a highly selective CXCR4 antagonist, as well as by an inhibitor of the MAP kinase pathway. In differentiated neurons, both SDF-1 and the glycoprotein of HIV, gp120, triggered activation of ERKs with similar kinetics. These effects were significantly inhibited by Pertussis toxin and the CXCR4 antagonist. Rat astrocytes also responded to SDF-1 signalling by phosphorylation of ERKs but, in contrast to cortical neurons, no kinase activation was induced by gp120. Thus neurons and astrocytes can respond differently to signalling by SDF-1 and/or gp120. As SDF-1 triggers directed migration of neuronal progenitors, this alpha chemokine may play a role in cortex development. In differentiated neurons, both natural and viral ligands of CXCR4 activate ERKs and may therefore influence neuronal function.

    • ") and extracellular receptor kinase (ERK) (Lazarini et al. 2000). CXCR4- mediated increases in ERK and Ca 2? signal transduction have been shown to promote neuronal migration and differentiation (Lazarini et al. 2000). Further, ERK tyrosine phosphorylation has also been shown to promote neuronal survival (Volosin et al. 2006) and to be the main mediator of neurotrophic factor-induced neuritic morphogenesis (Naska et al. 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: Human immunodeficiency virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorder (HAND) which includes minor neurocognitive disorders or a more severe form of motor and cognitive impairments. Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of mild forms of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in individuals with HAND. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes this disorder. A number of HIV proteins has been shown to be released from HIV-infected cells. Moreover, these proteins have been shown to possess neurotoxic properties. This review describes new evidence of a direct interaction of the HIV protein gp120 with neurons, which might play a role in the etiopathology of HAND.
    Full-text · Article · Sep 2011 · Neurotoxicity Research
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    • "centration was found effective in previous studies on dissociated cortical neuronal progenitors in rat embryo (Lazarini et al., 2000). To examine whether the effects of CXCR4 were mediated by its known ligand SDF-1, new treatment groups were created (addition of 10 nM SDF-1 only, AMD3100 + 10 nM SDF-1, AMD3100 + 100 nM SDF-1). "
    [Show abstract] [Hide abstract] ABSTRACT: Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 influence neuronal migration and have been identified in nasal regions. Gonadotropin releasing hormone-1 (GnRH-1) neurons migrate from nasal regions into the developing forebrain, where postnatally they control reproduction. This study examined the role of SDF-1/CXCR4 in development of the GnRH-1/olfactory systems. Migrating GnRH-1 neurons were CXCR4 immunopositive as were the fibers along which they migrate. SDF-1 transcripts were detected in olfactory epithelium and vomeronasal organ, while SDF-1 immunoreactivity highlighted the GnRH-1 migratory pathway. CXCR4-deficient mice showed a decrease in GnRH-1 cells at the nasal forebrain junction and in brain, but the overall migratory pathway remained intact, no ectopic GnRH-1 cells were detected and olfactory axons reached the olfactory bulb. To further characterize the influence of SDF-1/CXCR4 in the GnRH-1 system, nasal explants were used. CXCR4 expression in vitro was similar to that in vivo. SDF-1 was detected in a dorsal midline cell cluster as well as in migrating GnRH-1 cells. Treatment of explants with bicyclam AMD3100, a CXCR4 antagonist, attenuated GnRH-1 neuronal migration and sensory axon outgrowth. Moreover, the number of GnRH-1 neurons in the explant periphery was reduced. The effects were blocked by coincubation with SDF-1. Removal of midline SDF-1 cells did not alter directional outgrowth of olfactory axons. These results indicate that SDF-1/CXCR4 signaling in not necessary for olfactory axon guidance but rather influences sensory axon extension and GnRH-1 neuronal migration, and maintains GnRH-1 neuronal expression as the cells move away from nasal pit regions.
    Full-text · Article · Mar 2008 · Developmental Neurobiology
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    • "To determine whether the migration-promoting effect of CXCL12 on MGE-derived cells was mediated by its high-affinity receptor CXCR4, we next performed loss-of-function experiments. First, we applied AMD3100, a specific antagonist of CXCR4 (Donzella et al., 1998; Lazarini et al., 2000; Rubin et al., 2003), to the medium in coculture experiments. Analysis of these experiments revealed that treatment with the CXCR4 inhibitor completely abolished the motogenic effect produced by CXCL12 (n ϭ 14) (Fig. 5C, D, G). "
    [Show abstract] [Hide abstract] ABSTRACT: Functioning of the cerebral cortex requires the coordinated assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. Although much is known about the migration of interneurons from the subpallium to the cortex, our understanding of the mechanisms controlling their precise integration within the cortex is still limited. Here, we have investigated in detail the behavior of GABAergic interneurons as they first enter the developing cortex by using time-lapse videomicroscopy, slice culture, and in utero experimental manipulations and analysis of mouse mutants. We found that interneurons actively avoid the cortical plate for a period of approximately 48 h after reaching the pallium; during this time, interneurons disperse tangentially through the marginal and subventricular zones. Perturbation of CXCL12/CXCR4 signaling causes premature cortical plate invasion by cortical interneurons and, in the long term, disrupts their laminar and regional distribution. These results suggest that regulation of cortical plate invasion by GABAergic interneurons is a key event in cortical development, because it directly influences the coordinated formation of appropriate glutamatergic and GABAergic neuronal assemblies.
    Full-text · Article · Mar 2008 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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