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.
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REFERENCES
Snider, W. 1994. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638.
Barbacid, M. 1995. Neurotrophic factors and their receptors. Curr. Opinion Cell Biol. 7:148–155.
Snider, W. D., and Wright, D. E. 1996. Neurotrophins cause a new sensation. Neuron 16:229–232.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Chomczynski, P., and Sacchi, N. 1987. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162:156–159.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1023/A:1022434209787