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  • 1
    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
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1998
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 2
    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
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1997
    detail.hit.zdb_id: 1475274-8
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  • 3
    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
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2000
    detail.hit.zdb_id: 1475274-8
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  • 4
    Online Resource
    Online Resource
    Elsevier BV ; 2004
    In:  Progress in Neurobiology Vol. 72, No. 6 ( 2004-4), p. 373-398
    In: Progress in Neurobiology, Elsevier BV, Vol. 72, No. 6 ( 2004-4), p. 373-398
    Type of Medium: Online Resource
    ISSN: 0301-0082
    RVK:
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
    detail.hit.zdb_id: 1500673-6
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Wiley ; 2002
    In:  European Journal of Neuroscience Vol. 16, No. 1 ( 2002-07), p. 105-118
    In: European Journal of Neuroscience, Wiley, Vol. 16, No. 1 ( 2002-07), p. 105-118
    Abstract: Following axotomy, cerebellar Purkinje cells (PCs) do not elongate their axons, even in a favourable environment, and are resistant to death. They have no constitutive presence of common growth‐associated proteins, such as GAP‐43 and c‐Jun Previous experiments show that injured transgenic PCs overexpressing GAP‐43 exhibit a profuse sprouting along the axon and at its severed end. Nevertheless, the lesioned axons are unable to regenerate either spontaneously or into growth‐permissive environments. In addition, a considerable number of GAP‐43 transgenic PCs degenerate after injury. c‐Jun is an inducible transcription factor expressed in axotomized central neurons and regenerating peripheral neurons. It also contributes to programmed cell death during development. To test whether c‐Jun could modify the response of PCs to axotomy or enhance the growth/death phenomena of GAP‐43 Purkinje neurons, we generated transgenic mice overexpressing c‐Jun in PCs. However, c‐Jun upregulation did not affect the adult intact phenotype of these neurons and their regenerative and survival capabilities after axotomy. Also in the cross‐bred GAP‐43/c‐Jun mice, c‐Jun did not modify the response of GAP‐43 PCs to axotomy. By contrast, in organotypic cultures of cerebellum taken from 9‐day‐old‐pups, the survival capabilities of PCs overexpressing c‐Jun decreased, in association with a consistent c‐Jun phosphorylation. On the whole our data show that c‐Jun alone is unable to trigger regenerative or degenerative phenomena in PCs and suggest that the cellular action of this early gene in developing and mature neurons strongly depends on interplaying intracellular signals.
    Type of Medium: Online Resource
    ISSN: 0953-816X , 1460-9568
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 2005178-5
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  • 6
    Online Resource
    Online Resource
    Wiley ; 2003
    In:  European Journal of Neuroscience Vol. 18, No. 8 ( 2003-10), p. 2146-2158
    In: European Journal of Neuroscience, Wiley, Vol. 18, No. 8 ( 2003-10), p. 2146-2158
    Type of Medium: Online Resource
    ISSN: 0953-816X , 1460-9568
    Language: English
    Publisher: Wiley
    Publication Date: 2003
    detail.hit.zdb_id: 2005178-5
    SSG: 12
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