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. 1993 Mar 15;90(6):2222–2226. doi: 10.1073/pnas.90.6.2222

Ciliary neurotrophic factor prevents retrograde neuronal death in the adult central nervous system.

R E Clatterbuck 1, D L Price 1, V E Koliatsos 1
PMCID: PMC46058  PMID: 8460125

Abstract

The neurocytokine ciliary neurotrophic factor (CNTF) was described originally as an activity that supports the survival of neurons of the chicken ciliary ganglia in vitro. The widespread expression of CNTF and its principal binding protein, CNTF receptor alpha, in the central and peripheral nervous systems suggests a broader trophic role for this peptide. In the present study, we report that CNTF prevents axotomy-induced cell death of neurons in the anteroventral and anterodorsal thalamic nuclei of the adult rat. Using the polymerase chain reaction, we also demonstrate the presence of CNTF and CNTF receptor alpha mRNA in these same thalamic nuclei. The coincidence of CNTF and its receptor in a population of neurons responding to the factor suggests a paracrine function for CNTF. The present findings establish that CNTF has significant effects on neurons of the central nervous system in vivo and demonstrate that neurocytokines can prevent cell death in the adult central nervous system.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler R., Landa K. B., Manthorpe M., Varon S. Cholinergic neuronotrophic factors: intraocular distribution of trophic activity for ciliary neurons. Science. 1979 Jun 29;204(4400):1434–1436. doi: 10.1126/science.451576. [DOI] [PubMed] [Google Scholar]
  2. Barbin G., Manthorpe M., Varon S. Purification of the chick eye ciliary neuronotrophic factor. J Neurochem. 1984 Nov;43(5):1468–1478. doi: 10.1111/j.1471-4159.1984.tb05410.x. [DOI] [PubMed] [Google Scholar]
  3. Bazan J. F. Neuropoietic cytokines in the hematopoietic fold. Neuron. 1991 Aug;7(2):197–208. doi: 10.1016/0896-6273(91)90258-2. [DOI] [PubMed] [Google Scholar]
  4. Berkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., Rosenthal A. Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron. 1991 Nov;7(5):857–866. doi: 10.1016/0896-6273(91)90287-a. [DOI] [PubMed] [Google Scholar]
  5. Blottner D., Brüggemann W., Unsicker K. Ciliary neurotrophic factor supports target-deprived preganglionic sympathetic spinal cord neurons. Neurosci Lett. 1989 Nov 6;105(3):316–320. doi: 10.1016/0304-3940(89)90640-x. [DOI] [PubMed] [Google Scholar]
  6. Davis S., Aldrich T. H., Valenzuela D. M., Wong V. V., Furth M. E., Squinto S. P., Yancopoulos G. D. The receptor for ciliary neurotrophic factor. Science. 1991 Jul 5;253(5015):59–63. doi: 10.1126/science.1648265. [DOI] [PubMed] [Google Scholar]
  7. Domesick V. B. The fasciculus cinguli in the rat. Brain Res. 1970 May 20;20(1):19–32. doi: 10.1016/0006-8993(70)90150-2. [DOI] [PubMed] [Google Scholar]
  8. Ernsberger U., Sendtner M., Rohrer H. Proliferation and differentiation of embryonic chick sympathetic neurons: effects of ciliary neurotrophic factor. Neuron. 1989 Mar;2(3):1275–1284. doi: 10.1016/0896-6273(89)90312-7. [DOI] [PubMed] [Google Scholar]
  9. Fischer W., Björklund A. Loss of AChE- and NGFr-labeling precedes neuronal death of axotomized septal-diagonal band neurons: reversal by intraventricular NGF infusion. Exp Neurol. 1991 Aug;113(2):93–108. doi: 10.1016/0014-4886(91)90167-b. [DOI] [PubMed] [Google Scholar]
  10. Graeber M. B., Tetzlaff W., Streit W. J., Kreutzberg G. W. Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy. Neurosci Lett. 1988 Mar 10;85(3):317–321. doi: 10.1016/0304-3940(88)90585-x. [DOI] [PubMed] [Google Scholar]
  11. Hagg T., Quon D., Higaki J., Varon S. Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS. Neuron. 1992 Jan;8(1):145–158. doi: 10.1016/0896-6273(92)90116-u. [DOI] [PubMed] [Google Scholar]
  12. Hallbök F., Ibáez C. F., Persson H. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron. 1991 May;6(5):845–858. doi: 10.1016/0896-6273(91)90180-8. [DOI] [PubMed] [Google Scholar]
  13. Hefti F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci. 1986 Aug;6(8):2155–2162. doi: 10.1523/JNEUROSCI.06-08-02155.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hofmann H. D. Ciliary neuronotrophic factor stimulates choline acetyltransferase activity in cultured chicken retina neurons. J Neurochem. 1988 Jul;51(1):109–113. doi: 10.1111/j.1471-4159.1988.tb04842.x. [DOI] [PubMed] [Google Scholar]
  15. Hughes S. M., Lillien L. E., Raff M. C., Rohrer H., Sendtner M. Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture. Nature. 1988 Sep 1;335(6185):70–73. doi: 10.1038/335070a0. [DOI] [PubMed] [Google Scholar]
  16. Ip N. Y., Ibáez C. F., Nye S. H., McClain J., Jones P. F., Gies D. R., Belluscio L., Le Beau M. M., Espinosa R., 3rd, Squinto S. P. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3060–3064. doi: 10.1073/pnas.89.7.3060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson D. J. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. doi: 10.1016/0092-8674(92)90634-o. [DOI] [PubMed] [Google Scholar]
  18. Koliatsos V. E., Applegate M. D., Knüsel B., Junard E. O., Burton L. E., Mobley W. C., Hefti F. F., Price D. L. Recombinant human nerve growth factor prevents retrograde degeneration of axotomized basal forebrain cholinergic neurons in the rat. Exp Neurol. 1991 May;112(2):161–173. doi: 10.1016/0014-4886(91)90066-l. [DOI] [PubMed] [Google Scholar]
  19. Lieberman A. R. The axon reaction: a review of the principal features of perikaryal responses to axon injury. Int Rev Neurobiol. 1971;14:49–124. doi: 10.1016/s0074-7742(08)60183-x. [DOI] [PubMed] [Google Scholar]
  20. Lillien L. E., Sendtner M., Rohrer H., Hughes S. M., Raff M. C. Type-2 astrocyte development in rat brain cultures is initiated by a CNTF-like protein produced by type-1 astrocytes. Neuron. 1988 Aug;1(6):485–494. doi: 10.1016/0896-6273(88)90179-1. [DOI] [PubMed] [Google Scholar]
  21. Lin L. F., Mismer D., Lile J. D., Armes L. G., Butler E. T., 3rd, Vannice J. L., Collins F. Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science. 1989 Nov 24;246(4933):1023–1025. doi: 10.1126/science.2587985. [DOI] [PubMed] [Google Scholar]
  22. Lu B., Yokoyama M., Dreyfus C. F., Black I. B. NGF gene expression in actively growing brain glia. J Neurosci. 1991 Feb;11(2):318–326. doi: 10.1523/JNEUROSCI.11-02-00318.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Manthorpe M., Skaper S. D., Williams L. R., Varon S. Purification of adult rat sciatic nerve ciliary neuronotrophic factor. Brain Res. 1986 Mar 5;367(1-2):282–286. doi: 10.1016/0006-8993(86)91603-3. [DOI] [PubMed] [Google Scholar]
  24. Morganti-Kossmann M. C., Kossmann T., Wahl S. M. Cytokines and neuropathology. Trends Pharmacol Sci. 1992 Jul;13(7):286–291. doi: 10.1016/0165-6147(92)90087-m. [DOI] [PubMed] [Google Scholar]
  25. Oppenheim R. W., Prevette D., Yin Q. W., Collins F., MacDonald J. Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor. Science. 1991 Mar 29;251(5001):1616–1618. doi: 10.1126/science.2011743. [DOI] [PubMed] [Google Scholar]
  26. PEACOCK J. H., COMBS C. M. RETROGRADE CELL DEGENERATION IN DIENCEPHALIC AND OTHER STRUCTURES AFTER HEMIDECORTICATION OF RHESUS MONKEYS. Exp Neurol. 1965 Mar;11:367–399. doi: 10.1016/0014-4886(65)90055-5. [DOI] [PubMed] [Google Scholar]
  27. POWELL T. P., COWAN W. M. A NOTE ON RETROGRADE FIBRE DEGENERATION. J Anat. 1964 Oct;98:579–585. [PMC free article] [PubMed] [Google Scholar]
  28. Rende M., Muir D., Ruoslahti E., Hagg T., Varon S., Manthorpe M. Immunolocalization of ciliary neuronotrophic factor in adult rat sciatic nerve. Glia. 1992;5(1):25–32. doi: 10.1002/glia.440050105. [DOI] [PubMed] [Google Scholar]
  29. Saadat S., Sendtner M., Rohrer H. Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture. J Cell Biol. 1989 May;108(5):1807–1816. doi: 10.1083/jcb.108.5.1807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sendtner M., Kreutzberg G. W., Thoenen H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature. 1990 May 31;345(6274):440–441. doi: 10.1038/345440a0. [DOI] [PubMed] [Google Scholar]
  31. Smet P. J., Abrahamson I. K., Ressom R. E., Rush R. A. A ciliary neuronotrophic factor from peripheral nerve and smooth muscle which is not retrogradely transported. Neurochem Res. 1991 Jun;16(6):613–620. doi: 10.1007/BF00965546. [DOI] [PubMed] [Google Scholar]
  32. Squinto S. P., Aldrich T. H., Lindsay R. M., Morrissey D. M., Panayotatos N., Bianco S. M., Furth M. E., Yancopoulos G. D. Identification of functional receptors for ciliary neurotrophic factor on neuronal cell lines and primary neurons. Neuron. 1990 Dec;5(6):757–766. doi: 10.1016/0896-6273(90)90334-c. [DOI] [PubMed] [Google Scholar]
  33. Stöckli K. A., Lillien L. E., Näher-Noé M., Breitfeld G., Hughes R. A., Raff M. C., Thoenen H., Sendtner M. Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain. J Cell Biol. 1991 Oct;115(2):447–459. doi: 10.1083/jcb.115.2.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stöckli K. A., Lottspeich F., Sendtner M., Masiakowski P., Carroll P., Götz R., Lindholm D., Thoenen H. Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. Nature. 1989 Dec 21;342(6252):920–923. doi: 10.1038/342920a0. [DOI] [PubMed] [Google Scholar]
  35. Thoenen H. The changing scene of neurotrophic factors. Trends Neurosci. 1991 May;14(5):165–170. doi: 10.1016/0166-2236(91)90097-e. [DOI] [PubMed] [Google Scholar]
  36. Tuszynski M. H., Armstrong D. M., Gage F. H. Basal forebrain cell loss following fimbria/fornix transection. Brain Res. 1990 Feb 5;508(2):241–248. doi: 10.1016/0006-8993(90)90402-w. [DOI] [PubMed] [Google Scholar]
  37. Unsicker K., Grothe C., Westermann R., Wewetzer K. Cytokines in neural regeneration. Curr Opin Neurobiol. 1992 Oct;2(5):671–678. doi: 10.1016/0959-4388(92)90037-l. [DOI] [PubMed] [Google Scholar]
  38. Williams L. R., Vahlsing H. L., Lindamood T., Varon S., Gage F. H., Manthorpe M. A small-gauge cannula device for continuous infusion of exogenous agents into the brain. Exp Neurol. 1987 Mar;95(3):743–754. doi: 10.1016/0014-4886(87)90313-x. [DOI] [PubMed] [Google Scholar]
  39. Yoshida K., Gage F. H. Cooperative regulation of nerve growth factor synthesis and secretion in fibroblasts and astrocytes by fibroblast growth factor and other cytokines. Brain Res. 1992 Jan 8;569(1):14–25. doi: 10.1016/0006-8993(92)90364-f. [DOI] [PubMed] [Google Scholar]

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