Skip to main content
Log in

Expression of mRNAs for Neurotrophins (NGF, BDNF, and NT-3) and their Receptors (p75NGFR, Trk, TrkB, and TrkC) in Human Peripheral Neuropathies

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The steady-state mRNA levels of NGF, BDNF and NT-3, and the mRNA levels of their receptors p75NGFR, trk, trk,B and trkC were examined in various human peripheral neuropathies, to determine the correlation with myelinated fiber pathology and T cell and macrophage invasions in the diseased nerves. Steady state levels of p75NGFR mRNAs were significantly elevated in nerves with axonal pathology. In contrast, steady state levels of trkB and trkC mRNA levels were diminished, trk mRNA was not detected in the human nerves. The NGF, BDNF, and NT-3 mRNA levels were elevated in the diseased nerves. The increase in BDNF and NT-3 mRNA levels were proportional to the extent of invasion of the nerves by T cells and macrophages, but did not directly correlate with axonal nor demyelinating pathology, thus suggesting that inflammatory cell invasions are involved in the regulation of BDNF and NT-3 mRNA expressions. These neurotrophin and their receptor gene expressions in the diseased human nerves would be regulated by an underlying pathology-related process, and could play a role in peripheral nerve repair.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. Snider, W. 1994. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638.

    PubMed  Google Scholar 

  2. Barbacid, M. 1995. Neurotrophic factors and their receptors. Curr. Opinion Cell Biol. 7:148–155.

    PubMed  Google Scholar 

  3. Snider, W. D., and Wright, D. E. 1996. Neurotrophins cause a new sensation. Neuron 16:229–232.

    PubMed  Google Scholar 

  4. Airaksinen, M. S. Koltzenburg, M., Lewin, G. R., Masu, Y., Helbig, C., Wolf, E., Brem, G., Toyka, K. V., Thoenen, H. 1996. Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. Neuron 16:287–295.

    PubMed  Google Scholar 

  5. Maisonpierre, P. C., Belluscio, L., Squinto, S., Ip, N. Y., Furth, M. E., Lindsay, R. M., and Yancopoulos, G. D. 1990. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 247:1446–1451.

    PubMed  Google Scholar 

  6. Koliatsos, V. E., Clatterbuck, R. E., Winslow, J. W., Cayouette, M. H., and Price, D. L. 1993. Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron 10:359–367.

    PubMed  Google Scholar 

  7. Sendtner, M., Holtmann, B., Kolbeck, R., Thoenen, H., and Barde, Y. A. 1992. Brain-derived neurotrophic factor prevents the death of motoneurons in new-born rats after nerve section. Nature 360:757–759.

    PubMed  Google Scholar 

  8. Klein, R., Jing, S., Nanduri, V., O'Rourke, E., and Barbacid, M. 1991. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65:189–197.

    PubMed  Google Scholar 

  9. Kaplan, D., Hempstead, B. L., Matin-Zanca, D., Chao, M. V., and Parada, L. F. 1991. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252:554–557.

    PubMed  Google Scholar 

  10. Kaplan, D., Martin-Zanca, D., and Parada, L. 1991. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-on-cogene product induced by NGF. Nature 350:158–160.

    PubMed  Google Scholar 

  11. Klein, R., Nanduri, V., Jing, S., Lamballe, F., Tapley, P., Bryant, S., Cordon-Cardo, C., Jones, K. R., Reichardt, L. F., and Barbacid, M. 1991. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66: 395–403.

    PubMed  Google Scholar 

  12. Klein, R., Parada, L., Coulier, F., and Barbacid, M. 1989. trkB, a novel tyrosine protein kinase receptor expressed during mouse neuronal development. EMBO J. 8:3701–3709.

    PubMed  Google Scholar 

  13. Squinto, S. P., Stitt, T. N., Aldrich, T. H., Davis, S., Bianco, S. M., Radziejewski, C., Glass, D. J., Masiakowski, P., Furth, M. E., Valenzuela, D. M., DiStefano, P. S., and Yancopoulos, G. D. 1991. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell 65:885–893.

    PubMed  Google Scholar 

  14. Lamballe, F., Klein, R., and Barbacid, M. 1991. trkC, a new member of trk family of tyrosine protein kinase, is a receptor for neurotrophin-3. Cell 66:967–979.

    PubMed  Google Scholar 

  15. Middlemas, D. S., Lindberg, R. A., and Hunter, T. 1991 trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol. Cell Biol. 11:143–153.

    PubMed  Google Scholar 

  16. Valenzuela, D. M., Maisonpierre, P. C., Glass, D. J., Rojas, E., Nunez, L., Kong, Y., Gies, D. R., Stitt, T. N., Ip, N. Y., and Yancopoulos, G. D. 1993. Alternative forms of rat TrkC with different functional capabilities. Neuron 10:963–974.

    Article  PubMed  Google Scholar 

  17. Funakoshi, H., Frisén, J., Barbany, G., Timmusk, T., Zachrisson, O., Verge, V. M. K., and Persson, H. 1993. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J. Cell Biol. 123:455–465.

    Article  PubMed  Google Scholar 

  18. Taniuchi, M., Clark, H. B., and Johnson E. M. Jr. 1986. Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc. Natl. Acad. Sci. U.S.A. 83:4049–4098.

    PubMed  Google Scholar 

  19. Heumann, R., Korsching, S., Bandtlow, C., and Thoenen, H. 1987. Changes of nerve growth factor synthesis in non-neuronal cells in response to sciatic nerve transection. J. Cell Biol. 104:1623–1631.

    Article  PubMed  Google Scholar 

  20. Heumann, R., Lindholm, D., Bandtlow, C., Meyer, M., Radeke, M. J., Misko, T. P., Shooter, E., and Thenen, H. 1987. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad. Sci. USA 84:8735–8739.

    PubMed  Google Scholar 

  21. Matsuoka, I., Meyer, M., and Thoenen, H. 1991. Cell-type-specific regulation of nerve growth factor (NGF) synthesis in non-neuronal cells: comparison of Schwann cells with other cell types. J. Neurosci. 11:3165–3177.

    PubMed  Google Scholar 

  22. Meyer, M., Matsuoka, I., Wetmore, C., Olson, L., and Thoenen, H. 1992. Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J. Cell Biol. 119:45–54.

    Article  PubMed  Google Scholar 

  23. Yamamoto, M., Sobue, G., Li, M., Arakawa, Y., Mitsuma, T., and Kimata, K. 1993. Nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and low-affinity nerve growth factor receptor (LNGFR) mRNA levels in cultured rat Schwann cells; differential time-and dose-dependent regulation by cAMP. Neurosci. Lett. 152:37–40.

    Article  PubMed  Google Scholar 

  24. Sebert, M. E., and Shooter, E. M. 1993. Expression of mRNA for neurotrophic factors and their receptors in the rat dorsal root ganglion and sciatic nerve following nerve injury. J. Neurosci. Res. 36:357–367.

    PubMed  Google Scholar 

  25. Scarpini, E., Ross, A. H., Rosen, J. L., Brown, M. J., Rostami, A., Koprowski, H., and Lisak, R. P. 1988. Expression of nerve growth factor receptor during human peripheral nerve development. Dev. Biol. 125:301–310.

    Article  PubMed  Google Scholar 

  26. Sobue, G., Yasuda, T., Mitsuma, T., Ross, A., and Pleasure, D. 1988. Expression of nerve growth factor receptor in human peripheral neuropathies. Ann. Neurol. 24:64–72.

    PubMed  Google Scholar 

  27. Sobue, G., Yasuda, T., Mitsuma, T., and Pleasure, D. 1989. Nerve growth factor receptor immunoreactivity in the neuronal perikarya of human sensory and sympathetic nerve ganglia. Neurology 39:937–941.

    PubMed  Google Scholar 

  28. Muragaki, Y., Timothy, N., Leight, S. et al. 1995. Expression of trk receptors in the developing and adult human central and peripheral nervous system. J. Comp. Neurol. 365:387–397.

    Google Scholar 

  29. Shelton, D. L., Sutherland, J., Gripp, J., Camerato, T., Armanini, M. P., Phillips, H. S., Carroll, K., Spencer, S. D., and Levinson, A. D. 1995. Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J. Neurosci. 15:477–491.

    PubMed  Google Scholar 

  30. Yamamoto, M., Sobue, G., Mutoh, T., and Mitsuma, T. 1993. Gene expression of high-(p140trk) and low-affinity nerve growth factor receptor (LNGFR) in the adult and aged human peripheral nervous system. Neurosci. Lett. 158:39–43.

    Article  PubMed  Google Scholar 

  31. Yamamoto, M., Sobue, G., Yamamoto, K., Terao, S., and Mitsuma, T. 1996. Expression of mRNAs for neurotrophins and their receptors in the adult human peripheral nervous system and non-neuronal tissues. Neurochem. Res. 21:929–938.

    PubMed  Google Scholar 

  32. Chomczynski, P., and Sacchi, N. 1987. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162:156–159.

    PubMed  Google Scholar 

  33. Ullrich, A., Gray, A., Berman, C., and Dull, T. J. 1983. Human beta-nerve growth factor gene sequence highly homologous to that of mouse. Nature 303:821–825.

    Article  PubMed  Google Scholar 

  34. Maisonpierre, P. C., Le Beau, M. M., Espinosa, III R., Ip, N. Y. Belluscio, L., De La Monte, S. M., Squinto, S., Furth, M. E., and Yancopoulos, G. D. 1991. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10:558–568.

    Article  PubMed  Google Scholar 

  35. Johnson, D., Lanahan, A., Buck, C. R., Sehgal, A., Morgan, C., Mercer, E., Bothwell, M., and Chao, M. 1986. Expression and structure of the human NGF receptor. Cell 47:545–554.

    Article  PubMed  Google Scholar 

  36. Martin-Zanca, D., Oskam, R., Mitra, G., Copeland, T., and Barbacid, M. 1989. Molecular and biochemical characterization of the human trk proto-oncogene. Mol. Cell. Biol. 9:24–33.

    PubMed  Google Scholar 

  37. Adams, M. D., Kelley, J. M., Gocayne, J. D., Dubnick, M., Polymeropoulos, M. H., Xiao, H., Merril, C. R., Wu, A., Olde, B., Moreno, R. F., Kerlavage, A. R., McCombie, W. R., and Venter, J. C. 1991. Complementary DNA sequencing: expressed sequence tags and human genome project. Science 252:1651–1656.

    PubMed  Google Scholar 

  38. Doyu, M., Sobue, G., Ken, E., Kimata, K., Shinomura, T., Yamada, Y., Mitsuma, T., and Takahashi, A. 1993. Laminin A, B1 and B2 chain gene expression in transected and regenerating nerves: regulation by axonal signals. J. Neurochem. 60:543–551.

    PubMed  Google Scholar 

  39. Sobue, G., Hashizume, Y., Mukai, E., Hirayama, M., Mitsuma, T., and Takahashi, A. 1989. X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 112:209–232.

    PubMed  Google Scholar 

  40. Pulford, K. A. F., Rigney, E. M., Micklem, K. J., Jones, M., Stross, W. P., Gatter, K. C., and Mason, D. Y. 1989. KP-1: a new monoclonal antibody that detects a monocyte/macrophage associated antigen in routinely processed tissue sections. J. Clin. Pathol. 42:414–421.

    PubMed  Google Scholar 

  41. Terry, L. A., Brown, M. H., and Beverley, P. C. L. 1988. The monoclonal antibody, UCHL 1, recognize a 180,000 MW component of the human leucocyte-common antigen CD 45. Immunology 64:331–336.

    PubMed  Google Scholar 

  42. Ernfors, P., Rosario, C. M., Merlio, J. P., Grant, G., Aldskogius, H., and Persson, H. 1993. Expression of mRNAs for neurotrophin receptors in the dorsal root ganglion and spinal cord during development and following peripheral or central axotomy. Mol. Brain Res. 17:217–226.

    Article  PubMed  Google Scholar 

  43. Eide, F. F., Vining, E. R., Eide, B. L., Zang, K., Wang, X. Y., and Reichardt, L. F. 1996. Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J. Neurosci. 16:3123–3129.

    PubMed  Google Scholar 

  44. Bradley, J. L., Thomas, P. K., King, R. H. M., Muddle, J. R., Ward, J. D., Tesfaye, S., Boulton, A. J. M., Tsigos, C., and Young, R. J. 1995. Myelinated nerve fibre regeneration in diabetic sensory polyneuropathy: correlation with type of diabetes. Acta Neuropathol. 90:403–410.

    PubMed  Google Scholar 

  45. Frisén, J., Verge, V. M., Fried, K., Risling, M., Persson, H., Trotter, J., Hokfelt, T., and Lindholm, D. 1993. Characterization of glial trkB receptors: differential response to injury in the central and peripheral nervous system. Proc. Natl. Acad. Sci. USA 90:4971–4975.

    PubMed  Google Scholar 

  46. Mudo, G., Persson, H., Timmusk, T., Funakoshi, H., Bindoni, M., and Belluardo, N. 1993. Increased expression of trkB and trkC messenger RNAs in the rat forebrain after focal mechanical injury. Neuroscience 57:901–912.

    Article  PubMed  Google Scholar 

  47. Ehlers, M. D., Kaplan, D. R., Price, D. L., and Koliatsos, V. E. 1995. NGF-stimulated retrograde transport of trkA in the mammalian nervous system. J. Cell Biol. 130:149–156.

    Article  PubMed  Google Scholar 

  48. Rariquez-Tebar, A., Dechant, G., Gotz, R., and Barde, Y. A. 1992. Binding of neurotrophin-3 to its neuronal receptors and interactions with nerve growth factor and brain-derived neurotrophic factor. EMBO J. 3:917–922.

    Google Scholar 

  49. Wetmore, C., and Olson, L. 1995. Neuronal and nonneuronal expression of neurotrophins and their receptors in sensory and sympathetic ganglia suggest new intercellular trophic interactions. J. Comp. Neurol. 353:143–159.

    PubMed  Google Scholar 

  50. McMahon, S. B., Armanini, M. P., Ling, L. H., and Phillips, H. S. 1994. Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 12:1161–1171.

    Article  PubMed  Google Scholar 

  51. Apfel, S. C., Areggo, J. C., Lipson, L., and Kessler, L. A. 1992. Nerve growth factor prevents experimental cisplatin neuropathy. Ann. Neurol. 31:76–80.

    PubMed  Google Scholar 

  52. Gao, W. Q., Dybdal, N., Shinsky, N., Murnane, A., Schmelzer, C., Siegel, M., Keller, G., Hefti, F., Phillips, H. S., and Winslow, J. W. 1995. Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy. Ann. Neurol. 38:30–37.

    PubMed  Google Scholar 

  53. Russel, J. W., Windebank, A. J., and Podrats, J. L. 1994. Role of nerve growth factor in suramin neuropathy studied in vitro. Ann. Neurol. 36:221–228.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sobue, G., Yamamoto, M., Doyu, M. et al. Expression of mRNAs for Neurotrophins (NGF, BDNF, and NT-3) and their Receptors (p75NGFR, Trk, TrkB, and TrkC) in Human Peripheral Neuropathies. Neurochem Res 23, 821–829 (1998). https://doi.org/10.1023/A:1022434209787

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022434209787

Navigation