The Gene for Ciliary Neurotrophic Factor (CNTF) Maps to Murine Chromosome 19 and its Expression is Not Affected in the Hereditary Motoneuron Disease ‘Wobbler’ of the Mouse

Kaupmann, Klemens; Sendtner, Michael; Stöckli, K. A.; Jockusch, Harald

doi:10.1111/j.1460-9568.1991.tb00052.x

Cited by 13 publications

(4 citation statements)

References 28 publications

(11 reference statements)

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“…This 24-kD band might reflect posttranslationally modified CNTF (the molecular nature of this modification is not clear) which is released from Schwann cells during demyelination caused by axonal degeneration. This interpretation is supported by the finding that this second CNTF-immunoreactive band is also detectable in Western blots of sciatic nerve extracts of Wobbler mice (Kaupmann et al, 1991b). In this mouse mutant axonal degeneration of motoneurons and secondary demyelination of peripheral nerves results from a genetic defect (Duchen et al, 1968;Kaupmann et al, 1991a) and occurs without mechanical nerve lesion.…”

Section: Discussionmentioning

confidence: 89%

Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration.

Sendtner

Stöckli

Thoenen

1992

The Journal of Cell Biology

348

203

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Abstract. Ciliary neurotrophic factor (CNTF) is expressed in high quantifies in Schwann cells of peripheral nerves during postnatal development of the rat. The absence of a hydrophobic leader sequence and the immunohistochemical localization of CNTF within the cytoplasm of these cells indicate that the factor might not be available to responsive neurons under physiological conditions. However, CNTF supports the survival of a variety of embryonic neurons, including spinal motoneurons in culture. Moreover we have recently demonstrated that the exogenous application of CNTF protein to the lesioned facial nerve of the newborn rat rescued these motoneurons from cell death. These results indicate that CNTF might indeed play a major role in assisting the survival of lesioned neurons in the adult peripheral nervous system. Here we demonstrate that the CNTF mRNA and protein levels and the manner in which they are regulated are compatible with such a function in lesioned peripheral neurons. In particular, immunohistochemical analysis showed significant quantities of CNTF at extracellular sites after sciatic nerve lesion. Western blots and determination of CNTF biological activity of the same nerve segments indicate that extracellular CNTF seems to be biologically active. After nerve lesion CNTF mRNA levels were reduced to <5 % in distal regions of the sciatic nerve whereas CNTF bioactivity decreased to only one third of the original before-lesion levels. A gradual reincrease in Schwann cells occurred concomitant with regeneration.

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Section: Discussionmentioning

confidence: 89%

Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration.

Sendtner

Stöckli

Thoenen

1992

The Journal of Cell Biology

348

203

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“…Low but still significant levels are detectable in the brain stem, cerebellum, septum, hippocampus. striatum, midbrain, and thalamus/hypothalamus, (Stockli et al, 199 1;Ip et al, 1993a). Other areas ofthe brain, in particular the frontal cortex and retina, do not contain detectable levels of CNTF mRNA.…”

Section: Regulation Of Cntf Mrna Distribution and Tissue-specificmentioning

confidence: 99%

Ciliary neurotrophic factor

et al. 1994

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Ciliary neurotrophic factor (CNTF) was first identified and partially purified from embryonic chick eye tissues. Subsequently, it was shown that CNTF is also present in large amounts in sciatic nerves of adult rats and rabbits, which led to its final purification and cloning. CNTF is not secreted by the classical secretory pathway involving the endoplasmatic reticulum and Golgi complex, but can be detected in high quantities within the cytoplasm of myelinating Schwann cells and astrocytes using immunohistochemistry. CNTF supports survival and / or differentiation of a variety of neuronal cell types including sensory, sympathetic and motoneurons. Also, nonneuroanl cells, such as oligodendrocytes, microglial cells, liver cells, and skeletal muscle cells, respond to exogenously administered CNTF, both in vitro and in vivo. During development, expression of CNTF is very low, if indeed it is expressed at all, and the phenotype of mice lacking endogenous CNTF, suggesting that CNTF after inactivation of the CNTF gene by homologous recombination suggests that CNTF does not play a crucial role for responsive cells during embryonic development. However, motoneurons are lost postnatally in mice lacking endogenous CNTF, suggesting that CNTF acts physiologically on the maintenance of these cells. The ability of exogenous CNTF to protect against motoneuron loss following lesion or in other animal models indicates that CNTF might be useful in the treatment of human motoneuron disorders, provided appropriate means of administration can be found. 1994 John Wiley & Sons, Inc.

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“…The CNTF gene resides on chromosome 19 in the mouse (Kaupmann et al 1991) and on chromosome ll (Lam et al 1991) in man. A defect of this gene has not been identified so far as the primary cause of disease in any of the known mouse mutants or inherited forms of human motoneuron disease.…”

Section: Discussionmentioning

confidence: 99%

“…A defect of this gene has not been identified so far as the primary cause of disease in any of the known mouse mutants or inherited forms of human motoneuron disease. In pmn and wobbler mice, biologically active CNTF can be extracted from myelinated peripheral nerves (Kaupmann et al 1991~ Sendtner et al 1992a). In addition, postmartern tissue of human ALS patients show normal expression of CNTF mRNA and protein, at least in 10 cases which could be analyzed (Sendtner, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Actions of CNTF and neurotrophins on degenerating motoneurons: Preclinical studies and clinical implications

Sendtner

Dittrich

Hughes

et al. 1994

Journal of the Neurological Sciences

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Spinal motoneurons innervating skeletal muscle were amongst the first neurons shown to require the presence of their target cells to develop appropriately. Isolated embryonie chick and rat motoneurons have been used to identify neurotrophic factors and cytokines capable of supporting the survival of developing motoneurons. Such factors include ciliary neurotrophic factor (CNTF), which is present physiologically in high amounts in myelinating Schwann cells of peripheral nerves, and brain-derived neurotrophic factor (BDNF) which is synthesized in skeletal muscle and, after peripheral nerve lesion. in Schwann cells. These factors have been further analyzed for their physiological significance in maintaining motoneuron function in vivo, and for their potential therapeutic usefulness in degenerative motoneuron disease. Both CNTF and BDNF are capable of rescuing injured facial motoneurons in newbom rats. Furthermore, CNTF prolongs survival and improves motor function of pmn mice, an animal model for degenerative motoneuron disease, by preventing degeneration of motoneuron axons and somata. Thus treatment of human motoneuron disease with neurotrophic factors should be possible, provided that rational means for application of these factors can be established considering also the appearance of potential side effects.

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The Gene for Ciliary Neurotrophic Factor (CNTF) Maps to Murine Chromosome 19 and its Expression is Not Affected in the Hereditary Motoneuron Disease ‘Wobbler’ of the Mouse

Cited by 13 publications

References 28 publications

Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration.

Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration.

Ciliary neurotrophic factor

Actions of CNTF and neurotrophins on degenerating motoneurons: Preclinical studies and clinical implications

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