Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF

Müller, Adrienne; Hauk, Thomas G.; Leibinger, Marco; Marienfeld, Ralf; Fischer, Dietmar

doi:10.1016/j.mcn.2009.03.002

Cited by 162 publications

(156 citation statements)

References 52 publications

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“…Two putative intracellular activators of RAF signaling, BAG1 and Mst3b, have been shown to promote regenerative axon growth in the optic nerve (Planchamp et al, 2008;Lorber et al, 2009), but the expression of a constitutively active MEK1 did not drive any regeneration in the optic nerve (Pernet et al, 2005). Others have concluded that ERK activity promotes RGC axon regeneration via an indirect mechanism dependent on glial cells (Müller et al, 2009). Although it is likely that multiple mechanisms, direct as well as indirect, will contribute to axon regeneration in the inhibitory environment of the CNS, the current cacophonic state of the field is likely caused by the mainly indirect approaches of incomplete penetrance that have been taken by various laboratories.…”

Section: Discussionmentioning

confidence: 99%

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

O’Donovan¹,

Ma²,

Guo³

et al. 2014

J Cell Biol

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Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

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Section: Discussionmentioning

confidence: 99%

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

O’Donovan¹,

Ma²,

Guo³

et al. 2014

J Cell Biol

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“…16,27 Similarly, application of exogenous CNTF, LIF, and IL-6 mediates neuroprotection and stimulates axon regeneration in RGC cultures as well as the injured optic nerve in vivo, particularly upon continuous release from virally transduced cells. 26,[28][29][30][31] CNTF, LIF, and IL-6 belong to the family of interleukin-6 (IL-6)-type cytokines activating the signal transducing receptor glycoprotein 130 (gp130) (Figure 1), 32 which in the adult retina is mainly expressed in RGCs. 33 LIF requires direct interaction with the LIF-receptor (LIFR) to form a signaling complex with gp130.…”

Section: Introductionmentioning

confidence: 99%

“…Comparably, IL-6 binds to the IL-6 receptor to form a complex with two gp130 receptors. 27,32 Although all these receptor components are expressed by mature RGCs 16,26 and cytokines directly interact with RGCs in cell cultures, 16,27,31,34 expression of the α-receptors (LIFR, CNTFR, IL6R) is seemingly limited in RGCs. In fact, CNTFRα is reportedly downregulated in RGCs upon axotomy, potentially even decreasing their responsiveness towards this respective cytokine.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to JAK/STAT3, IL-6-like cytokines also stimulate the PI3K/AKT/mTOR pathway in RGCs. 31,36 Figure 2 Normally, mTOR activity declines in mature RGCs upon optic nerve injury, but is sustained upon IS, application of IL-6-type cytokines or, independently of cytokines, by genetic depletion of the intrinsic PI3K inhibitor PTEN. 17,17,42 Inhibition of mTOR by rapamycin markedly compromised optic nerve regeneration after PTEN knockout, 17 but only affected long-distance regeneration induced by IS.…”

Section: Introductionmentioning

confidence: 99%

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Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration

Fischer

2016

Eye

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Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons and die soon after optic nerve injury. Research over the last two decades has demonstrated that application of IL-6-like cytokines or activation of respective downstream signaling pathways promote neuroprotection and optic nerve regeneration. However, the overall beneficial effects of natural cytokines remain usually rather moderate, possibly due to intrinsic signaling pathway inhibitors, such as PTEN or SOCS3, or a limited expression of specific cytokine receptors in RGCs. It was recently demonstrated that directly targeting the gp130 receptor, a common signalling receptor of all IL-6-like cytokines, induces stronger RGC axon regeneration in vitro and in vivo than other known growth-promoting treatments such as inflammatory stimulation or PTEN knockout. Remarkably, continuous expression of hyper-IL-6 (hIL-6) upon intravitreal AAV injection after nerve injury enables long-distance axon regeneration, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Thus, AAV-mediated hIL-6 delivery is so far one of the strongest single, post-injury treatments for the promotion of optic nerve regeneration and may be suitable for the development of novel, clinically applicable therapeutic treatments for human patients.

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“…According to recent results, extracellular OM produced by macrophages may promote axonal elongation and regeneration (Yin et al, 2006); this theory was supported by the studies of Müller et al (2007Müller et al ( , 2009) and Benowitz and Yin (2008). However, more recent studies raise questions about the macrophage origin of OM (Hauk et al, 2008;Charalambous et al, 2008) and it remains to be demonstrated whether extracellular OM is able to promote axonal outgrowth or axonal regeneration also under normal conditions (Taylor et al, 2009).…”

Section: Discussionmentioning

confidence: 93%

Upregulated expression of oncomodulin, the beta isoform of parvalbumin, in perikarya and axons in the diencephalon of parvalbumin knockout mice

et al. 2010

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Abstract-The calcium-binding proteins parvalbumin, calbindin D-28k, calretinin and calcineurin are present in subsets of GABAergic gigantic calyciform presynaptic terminals of the reticular thalamic nucleus (RTN). Previously it was hypothesized that GABA and calcium-binding proteins including parvalbumin are not only colocalized in the same neuron subpopulation, but that GABA synthesis and parvalbumin expression could be also genetically regulated by a common mechanism. Moreover, parvalbumin expression levels could influence GABA synthesis. For this, we analyzed GABA immunoreactivity in RTN gigantic calyciform presynaptic terminals of parvalbumin-deficient (PV؊/؊) mice. With respect to GABA immunoreactivity we found no differences compared to wild-type animals. However, using a polyclonal parvalbumin antibody raised against full-length rat muscle parvalbumin on brain sections of PV؊/؊ mice, we observed paradoxical parvalbumin immunoreactivity in partly varicose axons in the diencephalon, mainly in the lamina medullaris externa surrounding the thalamus. A detailed immunohistochemical, biochemical and molecular biological analysis revealed this immunoreactivity to be the result of an upregulation of oncomodulin (OM), the mammalian beta isoform of parvalbumin in PV؊/؊ mice. In addition, OM was present in a sparse subpopulation of neurons in the thalamus and in the dentate gyrus. OM expression has not been observed before in neurons of the mammalian brain; its expression was restricted to outer hair cells in the organ of Corti. Our results indicate that the absence of parvalbumin has no major effect on the GABA-synthesizing system in RTN presynaptic terminals excluding a direct effect of parvalbumin on this regulation. However, a likely homeostatic mechanism is induced resulting in the upregulation of OM in selected axons and neuronal perikarya. Our results warrant further detailed investigations on the putative role of OM in the brain.

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Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF

Cited by 162 publications

References 52 publications

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration

Upregulated expression of oncomodulin, the beta isoform of parvalbumin, in perikarya and axons in the diencephalon of parvalbumin knockout mice

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