Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

Ozog, Mark A.; Modha, Geetanjalee; Church, John A.; Reilly, Rayne; Naus, Christian C.

doi:10.1074/jbc.m709065200

Cited by 12 publications

(8 citation statements)

References 83 publications

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“…Exogenous CNTF, on the other hand, had a minimal effect on NL corneal nerve regeneration, but greatly increased nerve-ending branching from nerve fibers in wounded DM corneas. Finally, we showed that CNTFRα is required for maintenance of the sub-basal nerve plexus in UW corneas and for nerve regeneration in the healing corneas Soluble forms of CNTFRα have been detected in serum and cerebrospinal fluid (44) and shown to enhance CNTF-mediated protection against neuronal death and neurite outgrowth (45). Soluble CNTFRα can reconstitute a high-affinity-type CNTFR complex (46).…”

Section: Discussionmentioning

confidence: 93%

Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea

Gao

Yan

Lee

et al. 2016

Journal of Clinical Investigation

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Diabetic peripheral neuropathy (DPN) often leads to neurotrophic ulcerations in the cornea and skin; however, the underlying cellular mechanisms of this complication are poorly understood. Here, we used post-wound corneal sensory degeneration and regeneration as a model and tested the hypothesis that diabetes adversely affects DC populations and infiltration, resulting in disrupted DC-nerve communication and DPN. In streptozotocin-induced type 1 diabetic mice, there was a substantial reduction in sensory nerve density and the number of intraepithelial DCs in unwounded (UW) corneas. In wounded corneas, diabetes markedly delayed sensory nerve regeneration and reduced the number of infiltrating DCs, which were a major source of ciliary neurotrophic factor (CNTF) in the cornea. While CNTF neutralization retarded reinnervation in normal corneas, exogenous CNTF accelerated nerve regeneration in the wounded corneas of diabetic mice and healthy animals, in which DCs had been locally depleted. Moreover, blockade of the CNTF-specific receptor CNTFRα induced sensory nerve degeneration and retarded regeneration in normal corneas. Soluble CNTFRα also partially restored the branching of diabetes-suppressed sensory nerve endings and regeneration in the diabetic corneas. Collectively, our data show that DCs mediate sensory nerve innervation and regeneration through CNTF and that diabetes reduces DC populations in UW and wounded corneas, resulting in decreased CNTF and impaired sensory nerve innervation and regeneration.

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Section: Discussionmentioning

confidence: 93%

Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea

Gao

Yan

Lee

et al. 2016

Journal of Clinical Investigation

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“…Another study, using the floxed CNTFR mouse line in which the CNTFR gene was conditionally disrupted, has shown that adult CNTF receptor signaling plays an essential role in motor neuron survival (Lee et al 2008). The coadministration of CNTF with soluble CNTFR protects against neuronal death and enhances neurite outgrowth (Ozog et al 2008). The reduction of Cntfr gene expression in Car9 -/-mice could contribute to the morphological phenotype observed in the central nervous system.…”

Section: Discussionmentioning

confidence: 98%

“…The corresponding protein, CNTFR, is a specific receptor for neurocytokine ciliary neurotrophic factor (CNTF). CNTFR and CNTF are involved in neurite growth and protection from neuronal death (Ozog et al 2008). In fact, CNTF is one of the most potent neuroprotective factors for developmental motor neurons in vitro.…”

Section: Discussionmentioning

confidence: 99%

Brain phenotype of carbonic anhydrase IX-deficient mice

et al. 2011

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Preliminary observations have suggested mild behavioral changes and a morphological disruption of brain histology in 1.5-year-old carbonic anhydrase IX (CA IX)-deficient (Car9 (-/-)) mice. These findings led us to design a 1-year follow-up study in which the behavior and brain histology of Car9 (-/-) and wild-type mice were monitored. Morphological analysis revealed vacuolar degenerative changes in the brains of Car9 (-/-) mice. The changes became visible at the age of eight to ten months. Behavioral tests showed that the Car9 (-/-) mice exhibited abnormal locomotor activity and poor performance in a memory test. To further identify the transcriptomic responses to CA IX deficiency in the brain, genome-wide cDNA microarray analyses were performed. Thirty-one and 37 genes were significantly up- or down-regulated, respectively, in the brain of Car9 (-/-) mice compared to the wild-type mice. Functional annotation revealed that the genes with increased expression were involved in several processes, such as RNA metabolism, and the genes with reduced expression were implicated in other important processes, including the regulation of cellular ion homeostasis. Notably, the biological processes "behavior" and "locomotory behavior" were the two prominent terms overrepresented among the down-regulated genes, which is consistent with the behavioral phenotype. These results suggest that CA IX may directly or indirectly play novel functions in brain tissue. Furthermore, the brain phenotype of Car9 (-/-) mice seems to be age-dependent. The results indicate that the functional changes precede the microscopic alterations in the brains of Car9 (-/-) mice.

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“…In the present study, our data suggests that CNTF induces process outgrowth from OT magnocellular neurons, but it remains to be determined if the Jak-STAT pathway is involved in CNTF-induced process outgrowth. However, in response to CNTF, others have demonstrated differential effects of the Jak-STAT, PI3-AKT, and MAPK-ERK pathways in mediating cell survival versus process outgrowth (Alonzi, et al, 2001, Ozog, et al, 2008, Sango, et al, 2008). Thus, CNTF may mediate differential neuroprotective responses via different intracellular signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Jak-STAT pathway prevents CNTF-mediated survival of axotomized oxytocinergic magnocellular neurons in organotypic cultures of the rat supraoptic nucleus

Askvig

Sudbeck

et al. 2013

Experimental Neurology

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Previous studies have demonstrated that ciliary neurotrophic factor (CNTF) enhances survival and process outgrowth from magnocellular neurons in the paraventricular (PVN) and the supraoptic (SON) nuclei. However, the mechanisms by which CNTF facilitates these processes remain to be determined. Therefore, the aim of this study was to identify the immediate signal transduction events that occur within the rat SON following administration of exogenous rat recombinant CNTF (rrCNTF) and to determine the contribution of those intracellular signaling pathway(s) to neuronal survival and process outgrowth, respectively. Immunohistochemical and Western blot analysis demonstrated that axonal injury and acute unilateral pressure injection of 100 ng/μl of rrCNTF directly over the rat SON resulted in a rapid and transient increase in phosphorylated-STAT3 (pSTAT3) in astrocytes but not neurons in the SON in vivo. Utilizing rat hypothalamic organotypic explant cultures, we then demonstrated that administration of 25 ng/ml rrCNTF for 14 days significantly increased the survival and process outgrowth of OT magnocellular neurons. In addition, pharmacological inhibition of the Jak-STAT pathway via AG490 and cucurbitacin I significantly reduced the survival of OT magnocellular neurons in the SON and PVN; however, the contribution of the Jak-STAT pathway to CNTF-mediated process outgrowth remains to be determined. Together, these data indicate that CNTF-induced survival of OT magnocellular neurons is mediated indirectly through astrocytes via the Jak-STAT signaling pathway.

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Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

Cited by 12 publications

References 83 publications

Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea

Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea

Brain phenotype of carbonic anhydrase IX-deficient mice

Inhibition of the Jak-STAT pathway prevents CNTF-mediated survival of axotomized oxytocinergic magnocellular neurons in organotypic cultures of the rat supraoptic nucleus

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