Peripheral Nerve Regeneration in CNTF Knockout Mice

Yao, Mike; Moir, Melinda S.; Wang, Michelle Z.; To, Michael P.; Terris, David J.

doi:10.1097/00005537-199908000-00015

Cited by 27 publications

(26 citation statements)

References 16 publications

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“…The neuroregenerative effects of Schwann cells thus matched or superceded any minimal axonal trauma sustained by the injection technique. These findings are consistent with numerous studies suggesting that Schwann cells affect neural regeneration in vivo through the elaboration of extracellular matrix proteins, 12,13,47 neurotrophic factors, 9,10,39,[48][49][50] and the cellular adhesion molecules L1, 28,38 N-CAM, 15,37 ninjurin, 34 and N-cadherin. 35,37,51,52 After nerve injury, Schwann cells typically upregulate N-CAM and L-1 expression and downregulate myelin formation.…”

Section: Discussionsupporting

confidence: 92%

Safe injection of cultured Schwann cells into peripheral nerve allografts

et al. 2000

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The effects of cultured host Schwann cells on axonal regeneration in peripheral nerve allografts were studied. Fischer rats served as recipient animals and Buffalo rats provided nerve allografts. Animals were randomized into 9 groups. Rats receiving tibial nerve isografts were left untreated (group I), or injected with isogeneic Fischer Schwann cells (group II) or placebo suspension (group III). Allografts obtained from Buffalo rats were left untreated (group IV), or received isogeneic Fischer Schwann cells (group V), 2 mg/kg Cyclosporin A and Fischer Schwann cells (group VI), 5 mg/kg Cyclosporin A (group VII), or 5 mg/kg Cyclosporin A with Schwann cells (group VIII). No Schwann cell tumors were identified 4 or 8 weeks postoperatively. Group IX animals, harvested 3 days postoperatively, demonstrated no evidence of injection injury. Schwann cells modestly improved axonal regeneration in both isografts and allografts and may have a clinical role in the treatment of peripheral nerve allografts. © 2000 Wiley‐Liss, Inc. MICROSURGERY 20:314–323 2000

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Section: Discussionsupporting

confidence: 92%

Safe injection of cultured Schwann cells into peripheral nerve allografts

et al. 2000

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“…The results provide new evidence that CNTF, besides functioning as a survival and lesion factor that can prevent neuronal cell death and potentiate neuronal regeneration (Sendtner et al, 1990;Sahenk et al, 1994;Kuzis and Eckenstein, 1996;Sendtner, 1999;Yao et al, 1999), contributes to the longterm maintenance of nerve fibers of adult mammalian alpha-motor neurons. Lack of CNTF leads to disruption of specific axonal structures that are in direct functional contact with the myelinating Schwann cells at the nodes of Ranvier and correlates with a premature onset of morphological changes signifying nerve fiber degeneration (Spencer and Schaumburg, 1978;Martini, 2001).…”

Section: Discussionmentioning

confidence: 84%

Early onset of degenerative changes at nodes of Ranvier in alpha‐motor axons of Cntf null (^−/−) mutant mice

Gatzinsky

Holtmann

Daraie

et al. 2003

Glia

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The nodes of Ranvier are sites of specific interaction between Schwann cells and axons. Besides their crucial role in transmission of action potentials, the nodes of Ranvier and in particular the paranodal axon-Schwann cell networks (ASNs) are thought to function as local centers in large motor axons for removal, degradation, and disposal of organelles. In order to test whether ciliary neurotrophic factor (CNTF), which is present at high levels in the Schwann cell cytoplasm, is involved in the maintenance of these structures, we have examined lumbar ventral root nerve fibers of alpha-motor neurons by electron microscopy in 3- and 9-month-old Cntf null ((-/-)) mutant mice. Nerve fibers and nodes of Ranvier in 3-month-old Cntf(-/-) mutants appeared morphologically normal, except that ASNs were more voluminous in the mutants than in wild-type control animals at this age. In 9-month-old Cntf(-/-) animals, morphological changes, such as reduction in nerve fiber and axon diameter, myelin sheath disruption, and loss of ASNs at nodes of Ranvier, were observed. These findings suggest that endogenous CNTF, in addition to its role in promoting motor neuron survival and regeneration, is needed for long-term maintenance of alpha-motor nerve fibers. The premature loss of paranodal ASNs in animals lacking CNTF, which seems to be a defect related to a disturbed interaction in the nodal region between the axon and its myelinating Schwann cells, could impede the maintenance of a normal milieu in the motor axon, preceding more general neuronal damage.

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“…CNTF receptors are essential for embryonic development and the receptor knockout phenotype in mice is embryonic lethal (DeChiara et al 1995). Defects in CNTF expression result in an impaired neural injury response in mice (Masu et al 1993;Yao et al 1999;Linker et al 2002) and decreased neuron numbers in embryonic chick (Ernsberger et al 1989;Finn et al 1998). In addition, a variety of neuronal, glial and muscle cell types show responses to CNTF in vivo or in vitro affecting neuronal phenotype, neurotransmitter receptor levels, neurotransmitter release, metabolism and survival (Adler et al 1979;Nishi and Berg 1981;Hofmann 1988;Hughes et al 1988;Ernsberger et al 1989;Halvorsen and Berg 1989;Sendtner et al 1992Sendtner et al , 1994Helgren et al 1994;Symes et al 1994;Stoop and Poo 1995;Koshlukova et al 1996;Finn et al 1998;Wang and Halvorsen 1998b;Lambert et al 2001).…”

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confidence: 99%

Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons

Kaur¹,

Lu²,

Ward³

et al. 2005

Journal of Neurochemistry

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Generation of reactive oxygen species (ROS) with the accumulation of oxidative damage has been implicated in neurodegenerative disease and in the degradation of nervous system function with age. Here we report that ROS inhibit the activity of ciliary neurotrophic factor (CNTF) in nerve cells. Treatment with hydrogen peroxide (H 2 O 2 ) as a generator of ROS inhibited CNTF-mediated Jak/STAT signaling in all cultured nerve cells tested, including chick ciliary ganglion neurons, chick neural retina, HMN-1 motor neuron hybrid cells, and SH-SY5Y and BE(2)-C human neuroblastoma cells. H 2 O 2 treatment of non-neuronal cells, chick skeletal muscle and HepG2 hepatoma cells, did not inhibit Jak/STAT signaling. The H 2 O 2 block of CNTF activity was seen at concentrations as low as 0.1 mM and within 15 min, and was reversible upon removal of H 2 O 2 from the medium. Also, two other mediators of oxidative stress, nitric oxide and rotenone, inhibited CNTF signaling. Treatment of neurons with H 2 O 2 and rotenone also inhibited interferon-c-mediated activation of Jak/STAT1. Depleting the intracellular stores of reduced glutathione by treatment of BE(2)-C cells with nitrofurantoin inhibited CNTF activity, whereas addition of reduced glutathione protected cells from the effects of H 2 O 2 . These results suggest that disruption of neurotrophic factor signaling by mediators of oxidative stress may contribute to the neuronal damage observed in neurodegenerative diseases and significantly affect the utility of CNTF-like factors as therapeutic agents in preventing nerve cell death. Keywords: ciliary neurotrophic factor, cytokine, gpl30, reactive oxygen species, signal transduction, tyrosine kinase. Signaling through the ciliary neurotrophic factor (CNTF) receptor has been implicated in the development, survival and maintenance of a broad range of neurons and glia in the PNS and CNS, as well as cardiac and skeletal muscle. CNTF receptors are essential for embryonic development and the receptor knockout phenotype in mice is embryonic lethal (DeChiara et al. 1995). Defects in CNTF expression result in an impaired neural injury response in mice (Masu et al. 1993;Yao et al. 1999;Linker et al. 2002) and decreased neuron numbers in embryonic chick (Ernsberger et al. 1989;Finn et al. 1998). In addition, a variety of neuronal, glial and muscle cell types show responses to CNTF in vivo or in vitro affecting neuronal phenotype, neurotransmitter receptor levels, neurotransmitter release, metabolism and survival (Adler et al.

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Peripheral Nerve Regeneration in CNTF Knockout Mice

Cited by 27 publications

References 16 publications

Safe injection of cultured Schwann cells into peripheral nerve allografts

Safe injection of cultured Schwann cells into peripheral nerve allografts

Early onset of degenerative changes at nodes of Ranvier in alpha‐motor axons of Cntf null (^−/−) mutant mice

Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons

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Peripheral Nerve Regeneration in CNTF Knockout Mice

Cited by 27 publications

References 16 publications

Safe injection of cultured Schwann cells into peripheral nerve allografts

Safe injection of cultured Schwann cells into peripheral nerve allografts

Early onset of degenerative changes at nodes of Ranvier in alpha‐motor axons of Cntf null (−/−) mutant mice

Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons

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Early onset of degenerative changes at nodes of Ranvier in alpha‐motor axons of Cntf null (^−/−) mutant mice