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  • 1
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    Online Resource
    Expression pattern of the transcription factor Olig2 in response to brain injuries: Implications for neuronal repair
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 50 ( 2005-12-13), p. 18183-18188
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 50 ( 2005-12-13), p. 18183-18188
    Abstract: Despite the presence of neural stem cells and ongoing neurogenesis in some regions of the adult mammalian brain, neurons are not replaced in most brain regions after injury. With the aim to unravel factors contributing to the failure of neurogenesis in the injured cerebral cortex, we examined the expression of cell fate determinants after acute brain injuries, such as stab wound or focal ischemia, and in a model of chronic amyloid deposition. Although none of the neurogenic factors, such as Pax6, Mash1, Ngn2, was detected in the injured parenchyma, we observed a strong up-regulation of the bHLH transcription factor Olig2, but not Olig1, upon acute and chronic injury. To examine the function of Olig2 in brain lesion, we injected retroviral vectors containing a dominant negative form of Olig2 into the lesioned cortex 2 days after a stab wound. Antagonizing Olig2 function resulted in a significant number of infected cells generating immature neurons that were not observed after injection of the control virus. These data, therefore, imply Olig2 as a repressor of neurogenesis in cells reacting to brain injury and open innovative perspectives toward evoking endogenous neuronal repair.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0506535102
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
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    SSG: 11
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  • 2
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    Online Resource
    Retrograde Regulation of Growth-Associated Gene Expression in Adult Rat Purkinje Cells by Myelin-Associated Neurite Growth Inhibitory Proteins
    Society for Neuroscience ; 1998
    In:  The Journal of Neuroscience Vol. 18, No. 19 ( 1998-10-01), p. 7912-7929
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 18, No. 19 ( 1998-10-01), p. 7912-7929
    Abstract: Axon regeneration requires that injured neurons reinitiate long-distance growth and upregulate specific genes. To address the question of whether inhibitory environmental cues along the axon could exert a negative, tonic downregulation of growth-associated genes, we have examined adult rat Purkinje cells, which are endowed with poor regenerative capabilities. First we have compared their response to axotomy with that of neurons of the inferior olive, lateral reticular nucleus, and deep cerebellar nuclei, all of which vigorously regenerate into growth-permissive transplants. These injured neurons upregulate the transcription factors c-Jun and JunD, GAP-43, and NADPH diaphorase. In contrast, most axotomized Purkinje cells fail to express any of these markers, showing that the strength of this response parallels the regenerative potential of the examined neuron populations. However, strong upregulation of the same genes can be induced in Purkinje cells after colchicine injection into the uninjured adult cerebellum, indicating that their expression could be controlled by retrograde signals. To assess whether myelin-associated neurite growth inhibitory proteins contribute to this regulation, we applied the neutralizing antibodies IN-1 against one of the main inhibitory components of central myelin (NI-250) either in vivo or in vitro to organotypic cerebellar cultures. Application of IN-1 antibodies induces the upregulation of c-Jun, JunD, and NADPH diaphorase in Purkinje cells, showing that their expression is suppressed constitutively by myelin-associated neurite growth inhibitors. Thus, the inhibitory activity of the IN-1 antigen on axon growth is not restricted to the control of growth cone motility but also involves a retrograde regulation of gene expression in adult central neurons.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.18-19-07912.1998
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1998
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
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    Online Resource
    Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy
    Oxford University Press (OUP) ; 2019
    In:  Brain Vol. 142, No. 7 ( 2019-07-01), p. 1905-1920
    Details
    In: Brain, Oxford University Press (OUP), Vol. 142, No. 7 ( 2019-07-01), p. 1905-1920
    Abstract: Allele-specific silencing by RNA interference (ASP-siRNA) holds promise as a therapeutic strategy for downregulating a single mutant allele with minimal suppression of the corresponding wild-type allele. This approach has been effectively used to target autosomal dominant mutations and single nucleotide polymorphisms linked with aberrantly expanded trinucleotide repeats. Here, we propose ASP-siRNA as a preferable choice to target duplicated disease genes, avoiding potentially harmful excessive downregulation. As a proof-of-concept, we studied autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) due to lamin B1 (LMNB1) duplication, a hereditary, progressive and fatal disorder affecting myelin in the CNS. Using a reporter system, we screened the most efficient ASP-siRNAs preferentially targeting one of the alleles at rs1051644 (average minor allele frequency: 0.45) located in the 3′ untranslated region of the gene. We identified four siRNAs with a high efficacy and allele-specificity, which were tested in ADLD patient-derived fibroblasts. Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels. Furthermore, small interfering RNA treatment abrogates the ADLD-specific phenotypes in fibroblasts and in two disease-relevant cellular models: murine oligodendrocytes overexpressing human LMNB1, and neurons directly reprogrammed from patients’ fibroblasts. In conclusion, we demonstrated that ASP-silencing by RNA interference is a suitable and promising therapeutic option for ADLD. Moreover, our results have a broad translational value extending to several pathological conditions linked to gene-gain in copy number variations.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awz139
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474117-9
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  • 4
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    Online Resource
    Distinct Roles of Nogo-A and Nogo Receptor 1 in the Homeostatic Regulation of Adult Neural Stem Cell Function and Neuroblast Migration
    Society for Neuroscience ; 2012
    In:  The Journal of Neuroscience Vol. 32, No. 49 ( 2012-12-05), p. 17788-17799
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 32, No. 49 ( 2012-12-05), p. 17788-17799
    Abstract: In the adult mammalian subventricular zone (SVZ), GFAP-positive neural stem cells (NSCs) generate neuroblasts that migrate tangentially along the rostral migratory stream (RMS) toward the olfactory bulb (OB). In the mouse brain, we found that the plasticity inhibitors Nogo-A and Nogo receptor 1 (NgR1) are differentially expressed in the SVZ–OB system, in which Nogo-A identifies immature neuroblasts and NgR1 germinal astrocytes. We therefore examined the role of Nogo-A and NgR1 in the regulation of neurogenesis. Pharmacological experiments show that Nogo-66/NgR1 interaction reduces the proliferation of NSCs. This is consistent with a negative-feedback loop, in which newly generated neurons modulate cell division of SVZ stem cells. Moreover, the Nogo-A–Δ20 domain promotes neuroblast migration toward the OB through activation of the Rho/ROCK (Rho-associated, coiled-coil containing protein kinase) pathway, without the participation of NgR1. Our findings reveal a new unprecedented function for Nogo-A and NgR1 in the homeostatic regulation of the pace of neurogenesis in the adult mouse SVZ and in the migration of neuroblasts along the RMS.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3142-12.2012
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2012
    detail.hit.zdb_id: 1475274-8
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  • 5
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    Online Resource
    Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants
    Society for Neuroscience ; 1997
    In:  The Journal of Neuroscience Vol. 17, No. 22 ( 1997-11-15), p. 8778-8791
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 17, No. 22 ( 1997-11-15), p. 8778-8791
    Abstract: B-50/GAP-43 is a nervous tissue-specific protein, the expression of which is associated with axon growth and regeneration. Its overexpression in transgenic mice produces spontaneous axonal sprouting and enhances induced remodeling in several neuron populations (Aigner et al., 1995; Holtmaat et al., 1995). We examined the capacity of this protein to increase the regenerative potential of injured adult central axons, by inducing targeted B-50/GAP-43 overexpression in Purkinje cells, which normally show poor regenerative capabilities. Thus, transgenic mice were produced in which B-50/GAP-43 overexpression was driven by the Purkinje cell-specific L7 promoter. Uninjured transgenic Purkinje cells displayed normal morphology, indicating that transgene expression does not modify the normal phenotype of these neurons. By contrast, after axotomy numerous transgenic Purkinje cells exhibited profuse sprouting along the axon and at its severed end. Nevertheless, despite these growth phenomena, which never occurred in wild-type mice, the severed transgenic axons were not able to regenerate, either spontaneously or into embryonic neural or Schwann cell grafts placed into the lesion site. Finally, although only a moderate Purkinje cell loss occurred in wild-type cerebella after axotomy, a considerable number of injured transgenic neurons degenerated, but they could be partially rescued by the different transplants placed into the lesion site. Thus, B-50/GAP-43 overexpression substantially modifies Purkinje cell response to axotomy, by inducing growth processes and decreasing their resistance to injury. However, the presence of this protein is not sufficient to enable these neurons to accomplish a full program of axon regeneration.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.17-22-08778.1997
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1997
    detail.hit.zdb_id: 1475274-8
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  • 6
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    Online Resource
    Application of Neutralizing Antibodies against NI-35/250 Myelin-Associated Neurite Growth Inhibitory Proteins to the Adult Rat Cerebellum Induces Sprouting of Uninjured Purkinje Cell Axons
    Society for Neuroscience ; 2000
    In:  The Journal of Neuroscience Vol. 20, No. 6 ( 2000-03-15), p. 2275-2286
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 20, No. 6 ( 2000-03-15), p. 2275-2286
    Abstract: The myelin-associated proteins NI-35/250 exert a powerful inhibition on axon regeneration, but their function exerted on intact neurons is still unclear. In the adult CNS these proteins are thought to regulate axon growth processes to confine plasticity within restricted regions and to prevent the formation of aberrant connections. We have recently shown that application of neutralizing IN-1 antibody Fab fragment against NI-35/250 proteins to the adult cerebellum induces the expression of injury/growth-associated markers in intact Purkinje cells. Here, we asked whether these cellular modifications are accompanied by growth phenomena of Purkinje neurites. A single intraparenchymal application of IN-1 Fab fragment to the adult cerebellum induces a profuse sprouting of Purkinje axons along their intracortical course. The newly formed processes spread to cover most of the granular layer depth. A significant axon outgrowth is evident 2 d after injection; it tends to increase at 5 and 7 d, but it is almost completely reversed after 1 month. No axonal modifications occur in control Fab-treated cerebella. The IN-1 Fab fragment-induced cellular changes and axon remodeling are essentially reproduced by applying affinity-purified antibody 472 raised against a peptide sequence of the recombinant protein NI-220, thus confirming the specificity of the applied treatments on these myelin-associated molecules. Functional neutralization of NI-35/250 proteins induces outgrowth from uninjured Purkinje neurites in the adult cerebellum. Together with previous observations, this suggests that these molecules regulate axonal plasticity to maintain the proper targeting of terminal arbors within specific gray matter regions.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.20-06-02275.2000
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2000
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 7
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    Online Resource
    Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 9 ( 2008-03-04), p. 3581-3586
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 9 ( 2008-03-04), p. 3581-3586
    Abstract: Reactive gliosis is the universal reaction to brain injury, but the precise origin and subsequent fate of the glial cells reacting to injury are unknown. Astrocytes react to injury by hypertrophy and up-regulation of the glial-fibrillary acidic protein (GFAP). Whereas mature astrocytes do not normally divide, a subpopulation of the reactive GFAP + cells does so, prompting the question of whether the proliferating GFAP + cells arise from endogenous glial progenitors or from mature astrocytes that start to proliferate in response to brain injury. Here we show by genetic fate mapping and cell type-specific viral targeting that quiescent astrocytes start to proliferate after stab wound injury and contribute to the reactive gliosis and proliferating GFAP + cells. These proliferating astrocytes remain within their lineage in vivo , while a more favorable environment in vitro revealed their multipotency and capacity for self-renewal. Conversely, progenitors present in the adult mouse cerebral cortex labeled by NG2 or the receptor for the platelet-derived growth factor (PDGFRα) did not form neurospheres after (or before) brain injury. Taken together, the first fate-mapping analysis of astrocytes in the adult mouse cerebral cortex shows that some astrocytes acquire stem cell properties after injury and hence may provide a promising cell type to initiate repair after brain injury.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0709002105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
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    Online Resource
    Heterogeneity and Bipotency of Astroglial-Like Cerebellar Progenitors along the Interneuron and Glial Lineages
    Society for Neuroscience ; 2015
    In:  The Journal of Neuroscience Vol. 35, No. 19 ( 2015-05-13), p. 7388-7402
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 35, No. 19 ( 2015-05-13), p. 7388-7402
    Abstract: Cerebellar GABAergic interneurons in mouse comprise multiple subsets of morphologically and neurochemically distinct phenotypes located at strategic nodes of cerebellar local circuits. These cells are produced by common progenitors deriving from the ventricular epithelium during embryogenesis and from the prospective white matter (PWM) during postnatal development. However, it is not clear whether these progenitors are also shared by other cerebellar lineages and whether germinative sites different from the PWM originate inhibitory interneurons. Indeed, the postnatal cerebellum hosts another germinal site along the Purkinje cell layer (PCL), in which Bergmann glia are generated up to first the postnatal weeks, which was proposed to be neurogenic. Both PCL and PWM comprise precursors displaying traits of juvenile astroglia and neural stem cell markers. First, we examine the proliferative and fate potential of these niches, showing that different proliferative dynamics regulate progenitor amplification at these sites. In addition, PCL and PWM differ in the generated progeny. GABAergic interneurons are produced exclusively by PWM astroglial-like progenitors, whereas PCL precursors produce only astrocytes. Finally, through in vitro , ex vivo , and in vivo clonal analyses we provide evidence that the postnatal PWM hosts a bipotent progenitor that gives rise to both interneurons and white matter astrocytes.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5255-14.2015
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2015
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 9
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    Online Resource
    Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human
    Oxford University Press (OUP) ; 2018
    In:  Brain Vol. 141, No. 7 ( 2018-07-01), p. 2055-2065
    Details
    In: Brain, Oxford University Press (OUP), Vol. 141, No. 7 ( 2018-07-01), p. 2055-2065
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awy111
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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