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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Jul 15;90(14):6711–6715. doi: 10.1073/pnas.90.14.6711

Coexpression of neurotrophins and their receptors in neurons of the central nervous system.

Z Kokaia 1, J Bengzon 1, M Metsis 1, M Kokaia 1, H Persson 1, O Lindvall 1
PMCID: PMC47002  PMID: 8341689

Abstract

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are neuronal survival molecules which utilize the Trk family of tyrosine kinase receptors. Using double-label in situ hybridization, we demonstrate that mRNAs for BDNF and its high-affinity receptor TrkB are coexpressed in hippocampal and cortical neurons. Also, a large number of neurons in these areas coexpress NGF and BDNF mRNAs. Epileptic seizures lead to increased levels of both BDNF/TrkB and NGF/BDNF mRNAs in double-labeled cells. Our results show that individual neurons of the central nervous system can coexpress neurotrophins and their receptors and produce two neurotrophic factors. These factors could support neuronal survival after brain insults, not only via retrograde transport but also through autocrine mechanisms.

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Selected References

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  1. Auer R. N., Siesjö B. K. Biological differences between ischemia, hypoglycemia, and epilepsy. Ann Neurol. 1988 Dec;24(6):699–707. doi: 10.1002/ana.410240602. [DOI] [PubMed] [Google Scholar]
  2. Ayer-LeLievre C., Olson L., Ebendal T., Seiger A., Persson H. Expression of the beta-nerve growth factor gene in hippocampal neurons. Science. 1988 Jun 3;240(4857):1339–1341. doi: 10.1126/science.2897715. [DOI] [PubMed] [Google Scholar]
  3. Ballarín M., Ernfors P., Lindefors N., Persson H. Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain. Exp Neurol. 1991 Oct;114(1):35–43. doi: 10.1016/0014-4886(91)90082-n. [DOI] [PubMed] [Google Scholar]
  4. Barde Y. A., Edgar D., Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1(5):549–553. doi: 10.1002/j.1460-2075.1982.tb01207.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barde Y. A. Trophic factors and neuronal survival. Neuron. 1989 Jun;2(6):1525–1534. doi: 10.1016/0896-6273(89)90040-8. [DOI] [PubMed] [Google Scholar]
  6. Bengzon J., Kokaia Z., Ernfors P., Kokaia M., Leanza G., Nilsson O. G., Persson H., Lindvall O. Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling. Neuroscience. 1993 Mar;53(2):433–446. doi: 10.1016/0306-4522(93)90207-v. [DOI] [PubMed] [Google Scholar]
  7. Bengzon J., Söderström S., Kokaia Z., Kokaia M., Ernfors P., Persson H., Ebendal T., Lindvall O. Widespread increase of nerve growth factor protein in the rat forebrain after kindling-induced seizures. Brain Res. 1992 Aug 7;587(2):338–342. doi: 10.1016/0006-8993(92)91016-8. [DOI] [PubMed] [Google Scholar]
  8. Cheng B., Mattson M. P. NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron. 1991 Dec;7(6):1031–1041. doi: 10.1016/0896-6273(91)90347-3. [DOI] [PubMed] [Google Scholar]
  9. Collazo D., Takahashi H., McKay R. D. Cellular targets and trophic functions of neurotrophin-3 in the developing rat hippocampus. Neuron. 1992 Oct;9(4):643–656. doi: 10.1016/0896-6273(92)90028-c. [DOI] [PubMed] [Google Scholar]
  10. DiStefano P. S., Friedman B., Radziejewski C., Alexander C., Boland P., Schick C. M., Lindsay R. M., Wiegand S. J. The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron. 1992 May;8(5):983–993. doi: 10.1016/0896-6273(92)90213-w. [DOI] [PubMed] [Google Scholar]
  11. Dreyfus C. F., Bernd P., Martinez H. J., Rubin S. J., Black I. B. GABAergic and cholinergic neurons exhibit high-affinity nerve growth factor binding in rat basal forebrain. Exp Neurol. 1989 May;104(2):181–185. doi: 10.1016/s0014-4886(89)80012-3. [DOI] [PubMed] [Google Scholar]
  12. Eccleston P. A., Funa K., Heldin C. H. Expression of platelet-derived growth factor (PDGF) and PDGF alpha- and beta-receptors in the peripheral nervous system: an analysis of sciatic nerve and dorsal root ganglia. Dev Biol. 1993 Feb;155(2):459–470. doi: 10.1006/dbio.1993.1044. [DOI] [PubMed] [Google Scholar]
  13. Ernfors P., Bengzon J., Kokaia Z., Persson H., Lindvall O. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron. 1991 Jul;7(1):165–176. doi: 10.1016/0896-6273(91)90084-d. [DOI] [PubMed] [Google Scholar]
  14. Ernfors P., Ibáez C. F., Ebendal T., Olson L., Persson H. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5454–5458. doi: 10.1073/pnas.87.14.5454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ernfors P., Wetmore C., Olson L., Persson H. Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron. 1990 Oct;5(4):511–526. doi: 10.1016/0896-6273(90)90090-3. [DOI] [PubMed] [Google Scholar]
  16. Ernfors Patrik, Persson Håkan. Developmentally Regulated Expression of HDNF/NT-3 mRNA in Rat Spinal Cord Motoneurons and Expression of BDNF mRNA in Embryonic Dorsal Root Ganglion. Eur J Neurosci. 1991;3(10):953–961. doi: 10.1111/j.1460-9568.1991.tb00031.x. [DOI] [PubMed] [Google Scholar]
  17. Gall C. M., Isackson P. J. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science. 1989 Aug 18;245(4919):758–761. doi: 10.1126/science.2549634. [DOI] [PubMed] [Google Scholar]
  18. Gall C., Murray K., Isackson P. J. Kainic acid-induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus. Brain Res Mol Brain Res. 1991 Jan;9(1-2):113–123. doi: 10.1016/0169-328x(91)90136-l. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Heldin C. H., Westermark B. Growth factors as transforming proteins. Eur J Biochem. 1989 Oct 1;184(3):487–496. doi: 10.1111/j.1432-1033.1989.tb15041.x. [DOI] [PubMed] [Google Scholar]
  21. Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F., Chao M. V. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678–683. doi: 10.1038/350678a0. [DOI] [PubMed] [Google Scholar]
  22. Hofer M., Pagliusi S. R., Hohn A., Leibrock J., Barde Y. A. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 1990 Aug;9(8):2459–2464. doi: 10.1002/j.1460-2075.1990.tb07423.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hohn A., Leibrock J., Bailey K., Barde Y. A. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature. 1990 Mar 22;344(6264):339–341. doi: 10.1038/344339a0. [DOI] [PubMed] [Google Scholar]
  24. Holtzman D. M., Li Y., Parada L. F., Kinsman S., Chen C. K., Valletta J. S., Zhou J., Long J. B., Mobley W. C. p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF. Neuron. 1992 Sep;9(3):465–478. doi: 10.1016/0896-6273(92)90184-f. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Isackson P. J., Huntsman M. M., Murray K. D., Gall C. M. BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron. 1991 Jun;6(6):937–948. doi: 10.1016/0896-6273(91)90234-q. [DOI] [PubMed] [Google Scholar]
  27. Jones K. R., Reichardt L. F. Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8060–8064. doi: 10.1073/pnas.87.20.8060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kaisho Y., Yoshimura K., Nakahama K. Cloning and expression of a cDNA encoding a novel human neurotrophic factor. FEBS Lett. 1990 Jun 18;266(1-2):187–191. doi: 10.1016/0014-5793(90)81536-w. [DOI] [PubMed] [Google Scholar]
  29. Kaplan D. R., Hempstead B. L., Martin-Zanca D., Chao M. V., Parada L. F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science. 1991 Apr 26;252(5005):554–558. doi: 10.1126/science.1850549. [DOI] [PubMed] [Google Scholar]
  30. Kaplan D. R., Martin-Zanca D., Parada L. F. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. 1991 Mar 14;350(6314):158–160. doi: 10.1038/350158a0. [DOI] [PubMed] [Google Scholar]
  31. Klein R., Conway D., Parada L. F., Barbacid M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell. 1990 May 18;61(4):647–656. doi: 10.1016/0092-8674(90)90476-u. [DOI] [PubMed] [Google Scholar]
  32. Klein R., Jing S. Q., Nanduri V., O'Rourke E., Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189–197. doi: 10.1016/0092-8674(91)90419-y. [DOI] [PubMed] [Google Scholar]
  33. Klein R., Lamballe F., Bryant S., Barbacid M. The trkB tyrosine protein kinase is a receptor for neurotrophin-4. Neuron. 1992 May;8(5):947–956. doi: 10.1016/0896-6273(92)90209-v. [DOI] [PubMed] [Google Scholar]
  34. Klein R., Nanduri V., Jing S. A., Lamballe F., Tapley P., Bryant S., Cordon-Cardo C., Jones K. R., Reichardt L. F., Barbacid M. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell. 1991 Jul 26;66(2):395–403. doi: 10.1016/0092-8674(91)90628-c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kokaia M., Bengzon J., Kalén P., Lindvall O. Noradrenergic mechanisms in hippocampal kindling with rapidly recurring seizures. Brain Res. 1989 Jul 10;491(2):398–402. doi: 10.1016/0006-8993(89)90079-6. [DOI] [PubMed] [Google Scholar]
  36. Lamballe F., Klein R., Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991 Sep 6;66(5):967–979. doi: 10.1016/0092-8674(91)90442-2. [DOI] [PubMed] [Google Scholar]
  37. Lauterborn J. C., Isackson P. J., Gall C. M. Nerve growth factor mRNA-containing cells are distributed within regions of cholinergic neurons in the rat basal forebrain. J Comp Neurol. 1991 Apr 15;306(3):439–446. doi: 10.1002/cne.903060308. [DOI] [PubMed] [Google Scholar]
  38. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., Barde Y. A. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989 Sep 14;341(6238):149–152. doi: 10.1038/341149a0. [DOI] [PubMed] [Google Scholar]
  39. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987 Sep 4;237(4819):1154–1162. doi: 10.1126/science.3306916. [DOI] [PubMed] [Google Scholar]
  40. Lindvall O., Ernfors P., Bengzon J., Kokaia Z., Smith M. L., Siesjö B. K., Persson H. Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):648–652. doi: 10.1073/pnas.89.2.648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lothman E. W., Hatlelid J. M., Zorumski C. F., Conry J. A., Moon P. F., Perlin J. B. Kindling with rapidly recurring hippocampal seizures. Brain Res. 1985 Dec 23;360(1-2):83–91. doi: 10.1016/0006-8993(85)91223-5. [DOI] [PubMed] [Google Scholar]
  42. Lu B., Buck C. R., Dreyfus C. F., Black I. B. Expression of NGF and NGF receptor mRNAs in the developing brain: evidence for local delivery and action of NGF. Exp Neurol. 1989 Jun;104(3):191–199. doi: 10.1016/0014-4886(89)90029-0. [DOI] [PubMed] [Google Scholar]
  43. Maisonpierre P. C., Belluscio L., Squinto S., Ip N. Y., Furth M. E., Lindsay R. M., Yancopoulos G. D. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. doi: 10.1126/science.247.4949.1446. [DOI] [PubMed] [Google Scholar]
  44. McDonald N. Q., Lapatto R., Murray-Rust J., Gunning J., Wlodawer A., Blundell T. L. New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor. Nature. 1991 Dec 5;354(6352):411–414. doi: 10.1038/354411a0. [DOI] [PubMed] [Google Scholar]
  45. Merlio J. P., Ernfors P., Jaber M., Persson H. Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system. Neuroscience. 1992 Dec;51(3):513–532. doi: 10.1016/0306-4522(92)90292-a. [DOI] [PubMed] [Google Scholar]
  46. Merlio J. P., Ernfors P., Kokaia Z., Middlemas D. S., Bengzon J., Kokaia M., Smith M. L., Siesjö B. K., Hunter T., Lindvall O. Increased production of the TrkB protein tyrosine kinase receptor after brain insults. Neuron. 1993 Feb;10(2):151–164. doi: 10.1016/0896-6273(93)90307-d. [DOI] [PubMed] [Google Scholar]
  47. Middlemas D. S., Lindberg R. A., Hunter T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol. 1991 Jan;11(1):143–153. doi: 10.1128/mcb.11.1.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Phillips H. S., Hains J. M., Laramee G. R., Rosenthal A., Winslow J. W. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. Science. 1990 Oct 12;250(4978):290–294. doi: 10.1126/science.1688328. [DOI] [PubMed] [Google Scholar]
  49. Rocamora N., Palacios J. M., Mengod G. Limbic seizures induce a differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3, in the rat hippocampus. Brain Res Mol Brain Res. 1992 Mar;13(1-2):27–33. doi: 10.1016/0169-328x(92)90041-9. [DOI] [PubMed] [Google Scholar]
  50. Rosenthal A., Goeddel D. V., Nguyen T., Lewis M., Shih A., Laramee G. R., Nikolics K., Winslow J. W. Primary structure and biological activity of a novel human neurotrophic factor. Neuron. 1990 May;4(5):767–773. doi: 10.1016/0896-6273(90)90203-r. [DOI] [PubMed] [Google Scholar]
  51. Sasahara M., Fries J. W., Raines E. W., Gown A. M., Westrum L. E., Frosch M. P., Bonthron D. T., Ross R., Collins T. PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell. 1991 Jan 11;64(1):217–227. doi: 10.1016/0092-8674(91)90223-l. [DOI] [PubMed] [Google Scholar]
  52. Schecterson L. C., Bothwell M. Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons. Neuron. 1992 Sep;9(3):449–463. doi: 10.1016/0896-6273(92)90183-e. [DOI] [PubMed] [Google Scholar]
  53. Smits A., Kato M., Westermark B., Nistér M., Heldin C. H., Funa K. Neurotrophic activity of platelet-derived growth factor (PDGF): Rat neuronal cells possess functional PDGF beta-type receptors and respond to PDGF. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8159–8163. doi: 10.1073/pnas.88.18.8159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Soppet D., Escandon E., Maragos J., Middlemas D. S., Reid S. W., Blair J., Burton L. E., Stanton B. R., Kaplan D. R., Hunter T. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell. 1991 May 31;65(5):895–903. doi: 10.1016/0092-8674(91)90396-g. [DOI] [PubMed] [Google Scholar]
  55. 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. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell. 1991 May 31;65(5):885–893. doi: 10.1016/0092-8674(91)90395-F. [DOI] [PubMed] [Google Scholar]
  56. Timmusk T., Palm K., Metsis M., Reintam T., Paalme V., Saarma M., Persson H. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron. 1993 Mar;10(3):475–489. doi: 10.1016/0896-6273(93)90335-o. [DOI] [PubMed] [Google Scholar]
  57. Wetmore C., Cao Y. H., Pettersson R. F., Olson L. Brain-derived neurotrophic factor: subcellular compartmentalization and interneuronal transfer as visualized with anti-peptide antibodies. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9843–9847. doi: 10.1073/pnas.88.21.9843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Whittemore S. R., Friedman P. L., Larhammar D., Persson H., Gonzalez-Carvajal M., Holets V. R. Rat beta-nerve growth factor sequence and site of synthesis in the adult hippocampus. J Neurosci Res. 1988 Aug;20(4):403–410. doi: 10.1002/jnr.490200402. [DOI] [PubMed] [Google Scholar]
  59. Yeh H. J., Ruit K. G., Wang Y. X., Parks W. C., Snider W. D., Deuel T. F. PDGF A-chain gene is expressed by mammalian neurons during development and in maturity. Cell. 1991 Jan 11;64(1):209–216. doi: 10.1016/0092-8674(91)90222-k. [DOI] [PubMed] [Google Scholar]
  60. Zafra F., Hengerer B., Leibrock J., Thoenen H., Lindholm D. Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 1990 Nov;9(11):3545–3550. doi: 10.1002/j.1460-2075.1990.tb07564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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