Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal gliain vivo

Adel, Brian A. van; Arnold, Jennifer M.; Phipps, J.; Doering, Laurie C.; Ball, Alexander K.

doi:10.1002/neu.20117

Cited by 71 publications

(40 citation statements)

References 82 publications

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“…Part of these phenotypic changes has been reported previously at shorter time periods using injections of recombinant CNTF (see Introduction) and adenovirusmediated gene transfer of CNTF in the rat striatum (Lisovoski et al, 1997) and retina (van Adel et al, 2005). In addition, the changes in the phenotype of astrocytes were reproduced in our in vitro model of primary striatal neuron/astrocyte cultures, demonstrating that whatever the delivery system used, extracellular Figure 6.…”

Section: Discussionsupporting

confidence: 69%

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

Escartin¹,

Brouillet²,

Gubellini³

et al. 2006

J. Neurosci.

111

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To study the functional role of activated astrocytes in glutamate homeostasis in vivo, we used a model of sustained astrocytic activation in the rat striatum through lentiviral-mediated gene delivery of ciliary neurotrophic factor (CNTF). CNTF-activated astrocytes were hypertrophic, expressed immature intermediate filament proteins and highly glycosylated forms of their glutamate transporters GLAST and GLT-1. CNTF overexpression produced a redistribution of GLAST and GLT-1 into raft functional membrane microdomains, which are important for glutamate uptake. In contrast, CNTF had no detectable effect on the expression of a number of neuronal proteins and on the spontaneous glutamatergic transmission recorded from striatal medium spiny neurons. These results were replicated in vitro by application of recombinant CNTF on a mixed neuron/astrocyte striatal culture. Using microdialysis in the rat striatum, we found that the accumulation of extracellular glutamate induced by quinolinate (QA) was reduced threefold with CNTF. In line with this result, CNTF significantly increased QA-induced [ 18 F]-fluoro-2-deoxyglucose uptake, an indirect index of glutamate uptake by astrocytes. Together, these data demonstrate that CNTF activation of astrocytes in vivo is associated with marked phenotypic and molecular changes leading to a better handling of increased levels of extracellular glutamate. Activated astrocytes may therefore be important prosurvival agents in pathological conditions involving defects in glutamate homeostasis.

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Section: Discussionsupporting

confidence: 69%

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

Escartin¹,

Brouillet²,

Gubellini³

et al. 2006

J. Neurosci.

111

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“…Beyond that, many studies have shown that exogenous CNTF and LIF have significant protective effects on injured ganglion cells and photoreceptors (see e.g. Cayouette et al, 1998;Mey and Thanos, 1993;M€ uller et al, 2009;Ueki et al, 2008;van Adel et al, 2005). Thus, upregulation of CNTF and LIF in activated M€ uller cells may in turn strongly influence neuronal responses to injury.…”

Section: Discussionmentioning

confidence: 95%

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Kirsch

Trautmann

Ernst

et al. 2010

Glia

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Ciliary neurotrophic factor (CNTF) and the related cytokine leukemia inhibitory factor (LIF) have been implicated in regulating astrogliosis following CNS lesions. Application of the factors activates astrocytes in vivo and in vitro, and their expression as well as their receptors is upregulated after brain injury. Here, we investigated their function by studying Müller cell activation induced by optic nerve crush in CNTF- and LIF-deficient mice, and in animals with deficiencies in cytokine signaling pathways. In the retina of CNTF(-/-) mice, basal GFAP expression was reduced, but unexpectedly, injury-induced upregulation in activated Müller cells was increased during the first 3 days after lesion as compared to wild-type animals and this corresponded with higher phosphorylation level of STAT3, an indicator of cytokine signaling. The observation that LIF expression was strongly upregulated in CNTF(-/-) mice but not in wild-type animals following optic nerve lesion provided a possible explanation. In fact, additional ablation of the LIF gene in CNTF/LIF double knockout mice almost completely abolished early lesion-induced GFAP upregulation in Müller cells and STAT3 phosphorylation. Early Müller cell activation was also eliminated in LIF(-/-) mice, despite normal CNTF levels, as well as in mutants deficient in gp130/JAK/STAT signaling and in conditional STAT3 knockout mice. Our results demonstrate that LIF signaling via the gp130/JAK/STAT3 pathway is required for the initiation of the astrogliosis-like reaction of retinal Müller cells after optic nerve injury. A potential role of CNTF was possibly masked by a compensatory increase in LIF signaling in the absence of CNTF.

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“…164 Optic nerve transection also induced a time dependent loss of RGC, approximately 50% of RGC were lost 1 week after the insult, and 80% to 100% of RGC disappeared 2 weeks after optic nerve transaction. 159,[164][165][166][167][168][169][170][171][172][173][174][175] The death of RGC is mediated by apoptosis, which can be reduced by inhibition of apoptosis mediators. [176][177][178] A corresponding time-dependent disappearance of Thy-1 and NF-L mRNA was observed.…”

Section: Optic Nerve Injurymentioning

confidence: 99%

Rodent Models for Glaucoma Retinopathy and Optic Neuropathy

Pang

Clark

2007

Journal of Glaucoma

140

102

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Animal models are useful to elucidate the etiology and pathology of glaucoma and to develop novel and more effective therapies for the disease. Because of the substantial similarities between the rodent and primate eyes, and the advances of relevant study techniques, rat and mouse models of glaucoma have recently become popular as research tools. This review surveys research techniques used in the measurement of rodent intraocular pressure, and also the evaluation of pertinent morphologic, biochemical, and functional changes in the retina, optic nerve head, and optic nerve. This review further describes in detail the individual rodent models, some of which serve as surrogate models and do not entail ocular hypertension, whereas others involve transient or chronic increases of intraocular pressure. The technical considerations and theoretical concerns of these models, their advantages, and limitations, are also discussed.

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Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal gliain vivo

Cited by 71 publications

References 82 publications

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Rodent Models for Glaucoma Retinopathy and Optic Neuropathy

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