Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA.

Author information

Affiliations

  • 1. Max-Planck Institute for Psychiatry, Department of Neurochemistry, Martinsried, Germany.
      Authors
    • Meyer M 1
    (1 author)

The Journal of Cell Biology, 01 Oct 1992, 119(1):45-54
https://doi.org/10.1083/jcb.119.1.45 PMID: 1527172 PMCID: PMC2289627

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Abstract 

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are molecules which regulate the development and maintenance of specific functions in different populations of peripheral and central neurons, amongst them sensory neurons of neural crest and placode origin. Under physiological conditions NGF is synthesized by peripheral target tissues, whereas BDNF synthesis is highest in the CNS. This situation changes dramatically after lesion of peripheral nerves. As previously shown, there is a marked rapid increase in NGF mRNA in the nonneuronal cells of the damaged nerve. The prolonged elevation of NGF mRNA levels is related to the immigration of activated macrophages, interleukin-1 being the most essential mediator of this effect. Here we show that transsection of the rat sciatic nerve also leads to a very marked increase in BDNF mRNA, the final levels being even ten times higher than those of NGF mRNA. However, the time-course and spatial pattern of BDNF mRNA expression are distinctly different. There is a continuous slow increase of BDNF mRNA starting after day 3 post-lesion and reaching maximal levels 3-4 wk later. These distinct differences suggest different mechanisms of regulation of NGF and BDNF synthesis in non-neuronal cells of the nerve. This was substantiated by the demonstration of differential regulation of these mRNAs in organ culture of rat sciatic nerve and Schwann cell culture. Furthermore, using bioassays and specific antibodies we showed that cultured Schwann cells are a rich source of BDNF- and ciliary neurotrophic factor (CNTF)-like neurotrophic activity in addition to NGF. Antisera raised against a BDNF-peptide demonstrated BDNF-immunoreactivity in pure cultured Schwann cells, but not in fibroblasts derived from sciatic nerve.

Free full text 

Logo of jcellbiolLink to Publisher's site
J Cell Biol. 1992 Oct 1; 119(1): 45–54.
PMCID: PMC2289627
PMID: 1527172

Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA

Copyright and License information Disclaimer

Abstract

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are molecules which regulate the development and maintenance of specific functions in different populations of peripheral and central neurons, amongst them sensory neurons of neural crest and placode origin. Under physiological conditions NGF is synthesized by peripheral target tissues, whereas BDNF synthesis is highest in the CNS. This situation changes dramatically after lesion of peripheral nerves. As previously shown, there is a marked rapid increase in NGF mRNA in the nonneuronal cells of the damaged nerve. The prolonged elevation of NGF mRNA levels is related to the immigration of activated macrophages, interleukin-1 being the most essential mediator of this effect. Here we show that transsection of the rat sciatic nerve also leads to a very marked increase in BDNF mRNA, the final levels being even ten times higher than those of NGF mRNA. However, the time-course and spatial pattern of BDNF mRNA expression are distinctly different. There is a continuous slow increase of BDNF mRNA starting after day 3 post-lesion and reaching maximal levels 3-4 wk later. These distinct differences suggest different mechanisms of regulation of NGF and BDNF synthesis in non-neuronal cells of the nerve. This was substantiated by the demonstration of differential regulation of these mRNAs in organ culture of rat sciatic nerve and Schwann cell culture. Furthermore, using bioassays and specific antibodies we showed that cultured Schwann cells are a rich source of BDNF- and ciliary neurotrophic factor (CNTF)- like neurotrophic activity in addition to NGF. Antisera raised against a BDNF-peptide demonstrated BDNF-immunoreactivity in pure cultured Schwann cells, but not in fibroblasts derived from sciatic nerve.

Full Text

The Full Text of this article is available as a PDF (2.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Acheson A, Barker PA, Alderson RF, Miller FD, Murphy RA. Detection of brain-derived neurotrophic factor-like activity in fibroblasts and Schwann cells: inhibition by antibodies to NGF. Neuron. 1991 Aug;7(2):265–275. [Abstract] [Google Scholar]
  • Alderson RF, Alterman AL, Barde YA, Lindsay RM. Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron. 1990 Sep;5(3):297–306. [Abstract] [Google Scholar]
  • Assouline JG, Bosch P, Lim R, Kim IS, Jensen R, Pantazis NJ. Rat astrocytes and Schwann cells in culture synthesize nerve growth factor-like neurite-promoting factors. Brain Res. 1987 Jan;428(1):103–118. [Abstract] [Google Scholar]
  • Bandtlow CE, Heumann R, Schwab ME, Thoenen H. Cellular localization of nerve growth factor synthesis by in situ hybridization. EMBO J. 1987 Apr;6(4):891–899. [Europe PMC free article] [Abstract] [Google Scholar]
  • Barbin G, Manthorpe M, Varon S. Purification of the chick eye ciliary neuronotrophic factor. J Neurochem. 1984 Nov;43(5):1468–1478. [Abstract] [Google Scholar]
  • Barde YA. The nerve growth factor family. Prog Growth Factor Res. 1990;2(4):237–248. [Abstract] [Google Scholar]
  • Barth EM, Korsching S, Thoenen H. Regulation of nerve growth factor synthesis and release in organ cultures of rat iris. J Cell Biol. 1984 Sep;99(3):839–843. [Europe PMC free article] [Abstract] [Google Scholar]
  • Beuche W, Friede RL. The role of non-resident cells in Wallerian degeneration. J Neurocytol. 1984 Oct;13(5):767–796. [Abstract] [Google Scholar]
  • Brown MC, Perry VH, Lunn ER, Gordon S, Heumann R. Macrophage dependence of peripheral sensory nerve regeneration: possible involvement of nerve growth factor. Neuron. 1991 Mar;6(3):359–370. [Abstract] [Google Scholar]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [Abstract] [Google Scholar]
  • Collier TJ, Sladek CD, Gallagher MJ, Gereau RW, 4th, Springer JE. Diffusible factor(s) from adult rat sciatic nerve increases cell number and neurite outgrowth of cultured embryonic ventral mesencephalic tyrosine hydroxylase-positive neurons. J Neurosci Res. 1990 Nov;27(3):394–399. [Abstract] [Google Scholar]
  • Collier TJ, Springer JE. Co-grafts of embryonic dopamine neurons and adult sciatic nerve into the denervated striatum enhance behavioral and morphological recovery in rats. Exp Neurol. 1991 Dec;114(3):343–350. [Abstract] [Google Scholar]
  • Davies AM, Bandtlow C, Heumann R, Korsching S, Rohrer H, Thoenen H. Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor. Nature. 326(6111):353–358. [Abstract] [Google Scholar]
  • Ebendal T, Olson L, Seiger A, Hedlund KO. Nerve growth factors in the rat iris. Nature. 1980 Jul 3;286(5768):25–28. [Abstract] [Google Scholar]
  • 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. [Abstract] [Google Scholar]
  • 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. [Abstract] [Google Scholar]
  • Gage FH, Stenevi U, Carlstedt T, Foster G, Björklund A, Aguayo AJ. Anatomical and functional consequences of grafting mesencephalic neurons into a peripheral nerve "bridge" connected to the denervated striatum. Exp Brain Res. 1985;60(3):584–589. [Abstract] [Google Scholar]
  • Götz R, Kolbeck R, Lottspeich F, Barde YA. Production and characterization of recombinant mouse neurotrophin-3. Eur J Biochem. 1992 Mar 1;204(2):745–749. [Abstract] [Google Scholar]
  • Hagg T, Vahlsing HL, Manthorpe M, Varon S. Septohippocampal cholinergic axonal regeneration through peripheral nerve bridges: quantification and temporal development. Exp Neurol. 1990 Aug;109(2):153–163. [Abstract] [Google Scholar]
  • Heumann R, Thoenen H. Comparison between the time course of changes in nerve growth factor protein levels and those of its messenger RNA in the cultured rat iris. J Biol Chem. 1986 Jul 15;261(20):9246–9249. [Abstract] [Google Scholar]
  • Heumann R, Korsching S, Scott J, Thoenen H. Relationship between levels of nerve growth factor (NGF) and its messenger RNA in sympathetic ganglia and peripheral target tissues. EMBO J. 1984 Dec 20;3(13):3183–3189. [Europe PMC free article] [Abstract] [Google Scholar]
  • Heumann R, Korsching S, Bandtlow C, Thoenen H. Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection. J Cell Biol. 1987 Jun;104(6):1623–1631. [Europe PMC free article] [Abstract] [Google Scholar]
  • Heumann R, Lindholm D, Bandtlow C, Meyer M, Radeke MJ, Misko TP, Shooter E, Thoenen H. 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 U S A. 1987 Dec;84(23):8735–8739. [Europe PMC free article] [Abstract] [Google Scholar]
  • Hidaka H, Hagiwara M, Chijiwa T. Molecular pharmacology of protein kinases. Neurochem Res. 1990 Apr;15(4):431–434. [Abstract] [Google Scholar]
  • Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 1990 Aug;9(8):2459–2464. [Europe PMC free article] [Abstract] [Google Scholar]
  • Hofer MM, Barde YA. Brain-derived neurotrophic factor prevents neuronal death in vivo. Nature. 1988 Jan 21;331(6153):261–262. [Abstract] [Google Scholar]
  • Hohn A, Leibrock J, Bailey K, Barde YA. 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. [Abstract] [Google Scholar]
  • Hughes SM, Lillien LE, Raff MC, Rohrer H, Sendtner M. Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture. Nature. 1988 Sep 1;335(6185):70–73. [Abstract] [Google Scholar]
  • Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature. 1991 Mar 21;350(6315):230–232. [Abstract] [Google Scholar]
  • Johnson JE, Barde YA, Schwab M, Thoenen H. Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells. J Neurosci. 1986 Oct;6(10):3031–3038. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kromer LF, Cornbrooks CJ. Transplants of Schwann cell cultures promote axonal regeneration in the adult mammalian brain. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6330–6334. [Europe PMC free article] [Abstract] [Google Scholar]
  • Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989 Sep 14;341(6238):149–152. [Abstract] [Google Scholar]
  • Lemke G, Axel R. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell. 1985 Mar;40(3):501–508. [Abstract] [Google Scholar]
  • Lin LF, Mismer D, Lile JD, Armes LG, Butler ET, 3rd, Vannice JL, Collins F. Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science. 1989 Nov 24;246(4933):1023–1025. [Abstract] [Google Scholar]
  • Lindholm D, Heumann R, Meyer M, Thoenen H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987 Dec 17;330(6149):658–659. [Abstract] [Google Scholar]
  • Lindsay RM, Thoenen H, Barde YA. Placode and neural crest-derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor. Dev Biol. 1985 Dec;112(2):319–328. [Abstract] [Google Scholar]
  • Longo FM, Manthorpe M, Skaper SD, Lundborg G, Varon S. Neuronotrophic activities accumulate in vivo within silicone nerve regeneration chambers. Brain Res. 1983 Feb 14;261(1):109–116. [Abstract] [Google Scholar]
  • Maffei L, Carmignoto G, Perry VH, Candeo P, Ferrari G. Schwann cells promote the survival of rat retinal ganglion cells after optic nerve section. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1855–1859. [Europe PMC free article] [Abstract] [Google Scholar]
  • Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM, Yancopoulos GD. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. [Abstract] [Google Scholar]
  • Manthorpe M, Skaper SD, Williams LR, Varon S. Purification of adult rat sciatic nerve ciliary neuronotrophic factor. Brain Res. 1986 Mar 5;367(1-2):282–286. [Abstract] [Google Scholar]
  • Masiakowski P, Liu HX, Radziejewski C, Lottspeich F, Oberthuer W, Wong V, Lindsay RM, Furth ME, Panayotatos N. Recombinant human and rat ciliary neurotrophic factors. J Neurochem. 1991 Sep;57(3):1003–1012. [Abstract] [Google Scholar]
  • Matsuoka I, Meyer M, Thoenen H. Cell-type-specific regulation of nerve growth factor (NGF) synthesis in non-neuronal cells: comparison of Schwann cells with other cell types. J Neurosci. 1991 Oct;11(10):3165–3177. [Europe PMC free article] [Abstract] [Google Scholar]
  • Muir D, Gennrich C, Varon S, Manthorpe M. Rat sciatic nerve Schwann cell microcultures: responses to mitogens and production of trophic and neurite-promoting factors. Neurochem Res. 1989 Oct;14(10):1003–1012. [Abstract] [Google Scholar]
  • Perry VH, Brown MC, Gordon S. The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J Exp Med. 1987 Apr 1;165(4):1218–1223. [Europe PMC free article] [Abstract] [Google Scholar]
  • Porter S, Clark MB, Glaser L, Bunge RP. Schwann cells stimulated to proliferate in the absence of neurons retain full functional capability. J Neurosci. 1986 Oct;6(10):3070–3078. [Europe PMC free article] [Abstract] [Google Scholar]
  • 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. [Abstract] [Google Scholar]
  • Richardson PM, Ebendal T. Nerve growth activities in rat peripheral nerve. Brain Res. 1982 Aug 19;246(1):57–64. [Abstract] [Google Scholar]
  • Rodriguez-Tébar A, Dechant G, Barde YA. Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron. 1990 Apr;4(4):487–492. [Abstract] [Google Scholar]
  • Schwab ME, Thoenen H. Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors. J Neurosci. 1985 Sep;5(9):2415–2423. [Europe PMC free article] [Abstract] [Google Scholar]
  • Sendtner M, Arakawa Y, Stöckli KA, Kreutzberg GW, Thoenen H. Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival. J Cell Sci Suppl. 1991;15:103–109. [Abstract] [Google Scholar]
  • Shelton DL, Reichardt LF. Expression of the beta-nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7951–7955. [Europe PMC free article] [Abstract] [Google Scholar]
  • Shelton DL, Reichardt LF. Studies on the regulation of beta-nerve growth factor gene expression in the rat iris: the level of mRNA-encoding nerve growth factor is increased in irises placed in explant cultures in vitro, but not in irises deprived of sensory or sympathetic innervation in vivo. J Cell Biol. 1986 May;102(5):1940–1948. [Europe PMC free article] [Abstract] [Google Scholar]
  • Stöckli KA, Lillien LE, Näher-Noé M, Breitfeld G, Hughes RA, Raff MC, 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. [Europe PMC free article] [Abstract] [Google Scholar]
  • Taniuchi M, Clark HB, Johnson EM., Jr Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4094–4098. [Europe PMC free article] [Abstract] [Google Scholar]
  • Thanos Solon, Bähr Mathias, Barde Yves-Alain, Vanselow Jens. Survival and Axonal Elongation of Adult Rat Retinal Ganglion Cells. Eur J Neurosci. 1989 Jan;1(1):19–26. [Abstract] [Google Scholar]
  • Thoenen H. The changing scene of neurotrophic factors. Trends Neurosci. 1991 May;14(5):165–170. [Abstract] [Google Scholar]
  • Trapp BD, Hauer P, Lemke G. Axonal regulation of myelin protein mRNA levels in actively myelinating Schwann cells. J Neurosci. 1988 Sep;8(9):3515–3521. [Europe PMC free article] [Abstract] [Google Scholar]
  • van Horne CG, Strömberg I, Young D, Olson L, Hoffer B. Functional enhancement of intrastriatal dopamine-containing grafts by the co-transplantation of sciatic nerve tissue in 6-hydroxydopamine-lesioned rats. Exp Neurol. 1991 Aug;113(2):143–154. [Abstract] [Google Scholar]
  • Varon S, Skaper SD, Manthorpe M. Trophic activities for dorsal root and sympathetic ganglionic neurons in media conditioned by Schwann and other peripheral cells. Brain Res. 1981 Jan;227(1):73–87. [Abstract] [Google Scholar]
  • Villegas-Pérez MP, Vidal-Sanz M, Bray GM, Aguayo AJ. Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J Neurosci. 1988 Jan;8(1):265–280. [Europe PMC free article] [Abstract] [Google Scholar]
  • Weinmaster G, Lemke G. Cell-specific cyclic AMP-mediated induction of the PDGF receptor. EMBO J. 1990 Mar;9(3):915–920. [Europe PMC free article] [Abstract] [Google Scholar]
  • Wendt JS, Fagg GE, Cotman CW. Regeneration of rat hippocampal fimbria fibers after fimbria transection and peripheral nerve or fetal hippocampal implantation. Exp Neurol. 1983 Feb;79(2):452–461. [Abstract] [Google Scholar]
  • Wetmore C, Cao YH, Pettersson RF, 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. [Europe PMC free article] [Abstract] [Google Scholar]
  • Wetmore C, Ernfors P, Persson H, Olson L. Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization. Exp Neurol. 1990 Aug;109(2):141–152. [Abstract] [Google Scholar]
  • Windebank AJ, Blexrud MD. Biological activity of a new neuronal growth factor from injured peripheral nerve. Brain Res Dev Brain Res. 1989 Oct 1;49(2):243–251. [Abstract] [Google Scholar]
  • Windebank AJ, Poduslo JF. Neuronal growth factors produced by adult peripheral nerve after injury. Brain Res. 1986 Oct 15;385(1):197–200. [Abstract] [Google Scholar]
Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

Full text links 

Read article at publisher's site: https://doi.org/10.1083/jcb.119.1.45

Read article for free, from open access legal sources, via Unpaywall: http://jcb.rupress.org/content/119/1/45.full.pdfUnpaywall

Citations & impact 

Impact metrics

478
Citations
Jump to Citations

Citations of article over time

Article citations

Go to all (478) article citations

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

NINDS NIH HHS (1)