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CNS neurotrophins are biologically active and expressed by multiple cell types

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Abstract

Neutrotrophins are increasingly appreciated as potential modulators of neuronal function in the adult central nervous system (CNS). To describe the neurotrophin environment within the adult CNS, mRNA and protein expression patterns of neurotrophins-3 and −4 and of brain-derived neurotrophin were investigated in adult rat spinal cord and brain. Co-localization studies with CNS cell type-specific markers demonstrates that multiple cell types, including both neurons and glia, express these neurotrophins in the normal adult CNS. Although widely implicated in important CNS functions such as synaptic plasticity, biological activity of endogenous CNS neurotrophins has not been directly demonstrated. With a sensitive neurite outgrowth bioassay we demonstrate that CNS neurotrophins elicit neurite outgrowth and are biologically active. Moreover, antibody-blocking studies suggest that these three neurotrophins may comprise the bulk of adult CNS neurotrophic activity.

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References

  • M Alvarez-Dolado T Iglesias A Rodriguez-Pena J Bernal A Munoz (1994) ArticleTitleExpression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain Brain Res Mol Brain Res 27 249–257

    Google Scholar 

  • F Ausubel R Brent RE Kingston DD Moore JG Seidman JA Smith K Struhl (Eds) (1999) Current Protocols in Molecular Biology John Wiley and Sons New York

    Google Scholar 

  • A Balkowiec DM Katz (2000) ArticleTitleActivity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA In situ [In Process Citation] J Neurosci 20 7417–7423

    Google Scholar 

  • DK Binder MJ Routbort TE Ryan GD Yancopoulos JO McNamara (1999) ArticleTitleSelective inhibition of kindling development by intraventricular administration of TrkB receptor body J Neurosci 19 1424–1436

    Google Scholar 

  • IB Black (1999) ArticleTitleTrophic regulation of synaptic plasticity J Neurobiol 41 108–118

    Google Scholar 

  • MC Bohn (1999) ArticleTitleA commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy Biochem Pharmacol 57 135–142

    Google Scholar 

  • CR Buck HJ Martinez MV Chao IB Black (1988) ArticleTitleDifferential expression of the nerve growth factor receptor gene in multiple brain areas Dev Brain Res 44 259–268

    Google Scholar 

  • CR Buck KL Seburn TC Cope (2000) ArticleTitleNeurotrophin expression by spinal motoneurons in adult and developing rats J Comp Neurol 416 309–318

    Google Scholar 

  • JD Burrill L Moran MD Goulding H Saueressig (1997) ArticleTitlePAX2 is expressed in multiple spinal cord interneurons, including a population of EN1+ interneurons that require PAX6 for their development Development 124 4493–4503

    Google Scholar 

  • JM Canals N Checa S Marco P Akerud A Michels E Perez-Navarro E Tolosa E Arenas J Alberch (2001) ArticleTitleExpression of brain-derived neurotrophic factor in cortical neurons is regulated by striatal target area. J Neurosci 21 117–124

    Google Scholar 

  • PA Carr FJ Alvarez EA Leman RE Fyffe (1998) ArticleTitleCalbindin D28k expression in immunohistochemically identified Renshaw cells Neuroreport 9 2657–2661

    Google Scholar 

  • G Chen R Kolbeck YA Barde T Bonhoeffer A Kossel (1999) ArticleTitleRelative contribution of endogenous neurotrophins in hippocampal long- term potentiation J Neurosci 19 7983–7990

    Google Scholar 

  • S Cohen R Levi-Montalcini V Hamburger (1954) ArticleTitleA nerve growth-stimulating factor isolated from sarcomas 37 and 180 Proc Natl Acad Sci USA 40 1014–1018

    Google Scholar 

  • JC Conover JT Erickson DM Katz LM Bianchi WT Poueymirou J McClain L Pan M Helgren NY Ip P Boland et al. (1995) ArticleTitleNeuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4 Nature 375 235–238

    Google Scholar 

  • Cope TC, Seburn, KL, Buck CR 2001 How Does Nerve Injury Strengthen Ia-Motoneuron Synapses? In: Cope TC, Cope TC, eds. Cope TCs. Frontiers in Neuroscience: Motor Neurobiology of the Spinal Cord. New York: CRC Press. in press.

  • S Copray D Kernell (2000) ArticleTitleNeurotrophins and trk-receptors in adult rat spinal motoneurons: differences related to cell size but not to ‘slow/fast’ specialization Neurosci Lett 289 217–220

    Google Scholar 

  • E Debus K Weber M Osborn (1983) ArticleTitleMonoclonal antibodies specific for glial fibrillary acidic (GFA) protein and for each of the neurofilament triplet polypeptides Differentiation 25 193–203

    Google Scholar 

  • CF Dreyfus X Dai LD Lercher BR Racey WJ Friedman IB Black (1999) ArticleTitleExpression of neurotrophins in the adult spinal cord in vivo [In Process Citation] J Neurosci Res 56 1–7

    Google Scholar 

  • LF Eng RS Ghirnikar YL Lee (2000) ArticleTitleGlial fibrillary acidic protein: GFAP-thirty-one years (1969–2000) Neurochem Res 25 1439–1451

    Google Scholar 

  • J Ericson P Rashbass A Schedl S Brenner-Morton A Kawakami V Heyningen Particlevan TM Jessell J Briscoe (1997) ArticleTitlePax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling Cell 90 169–180

    Google Scholar 

  • P Ernfors KF Lee R Jaenisch (1994) ArticleTitleMice lacking brain-derived neurotrophic factor develop with sensory deficits Nature 368 147–150

    Google Scholar 

  • B Friedman S Hockfield JA Black KA Woodruff SG Waxman (1989) ArticleTitleIn situ demonstration of mature oligodendrocytes and their processes: an immunocytochemical study with a new monoclonal antibody rip. Glia 2 380–390

    Google Scholar 

  • WJ Friedman IB Black DR Kaplan (1998) ArticleTitleDistribution of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the postnatal rat brain: an immunocytochemical study Neuroscience 84 101–114

    Google Scholar 

  • CE Henderson (1996) ArticleTitleRole of neurotrophic factors in neuronal development Curr Opin Neurobiol 6 64–70

    Google Scholar 

  • M Iino K Goto W Kakegawa H Okado M Sudo S Ishiuchi A Miwa Y Takayasu I Saito K Tsuzuki S Ozawa (2001) ArticleTitleGlia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia Science 292 926–929

    Google Scholar 

  • RA Johnson AJ Okragly M Haak-Frendscho GS Mitchell (2000) ArticleTitleCervical dorsal rhizotomy increases brain-derived neurotrophic factor and neurotrophin-3 expression in the ventral spinal cord J Neurosci 20 RC77

    Google Scholar 

  • KR Jones I Farinas C Backus LF Reichardt (1994) ArticleTitleTargeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development Cell 76 989–999

    Google Scholar 

  • MP Junier P Legendre CV Esguerra M Tinel M Coulpier PA Dreyfus M Bahr (1998) ArticleTitleRegulation of growth factor gene expression in degenerating motoneurons of the murine mutant wobbler: a cellular patch-sampling/RT-PCR study Mol Cell Neurosci 12 168–177

    Google Scholar 

  • H Kang EM Schuman (1995) ArticleTitleLong-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus Science 267 1658–1662

    Google Scholar 

  • H Kang AA Welcher D Shelton EM Schuman (1997) ArticleTitle Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation Neuron 19 653–664

    Google Scholar 

  • R Klein I Silos-Santiago RJ Smeyne SA Lira R Brambilla S Bryant L Zhang WD Snider M Barbacid (1994) ArticleTitleDisruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements Nature 368 249–251

    Google Scholar 

  • F Lamballe RJ Smeyne M Barbacid (1994) ArticleTitleDevelopmental expression of trkC, the neurotrophin-3 receptor, in the mammalian nervous system J Neurosci 14 14–28

    Google Scholar 

  • AKT Law V Pencea CR Buck MB Luskin (1999) ArticleTitleNeurogenesis and neuronal migration in the neonatal rat forebrain anterior subventricular zone do not require GFAP-positive astrocytes Devel. Biol. 216 622–634

    Google Scholar 

  • J Leibrock F Lottspeich A Hohn M Hofer B Hengerer P Masiakowski H Thoenen YA Barde (1989) ArticleTitleMolecular cloning and expression of brain-derived neurotrophic factor Nature 341 149–152

    Google Scholar 

  • R Levi-Montalcini (1987) ArticleTitleThe nerve growth factor 35 years later Science 237 1154–1162

    Google Scholar 

  • JM Levine A Nishiyama (1996) ArticleTitleThe NG2 chondroitin sulfate proteoglycan: a multifunctional proteoglycan associated with immature cells Perspect Dev Neurobiol 3 245–259

    Google Scholar 

  • GR Lewin YA Barde (1996) ArticleTitlePhysiology of the neurotrophins Annu Rev Neurosci 19 289–317

    Google Scholar 

  • X Liu P Ernfors H Wu R Jaenisch (1995) ArticleTitleSensory but not motor neuron deficits in mice lacking NT4 and BDNF Nature 375 238–241

    Google Scholar 

  • T Manabe S Kaneko M Kuno (1989) ArticleTitleDisuse-induced enhancement of Ia synaptic transmission in spinal motoneurons of the rat J Neurosci 9 2455–2461

    Google Scholar 

  • AM McAllister LC Katz DC. Lo (1999) ArticleTitleNeurotrophins and synaptic plasticity [In Process Citation] Annu Rev Neurosci 22 295–318

    Google Scholar 

  • RJ McKeon MJ Jurynec CR Buck (1999) ArticleTitleThe chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar J Neurosci 19 10778–10788

    Google Scholar 

  • LM Mendell RD Johnson JB Munson (1999) ArticleTitleNeurotrophin modulation of the monosynaptic reflex after peripheral nerve transection J Neurosci 19 3162–3170

    Google Scholar 

  • CE Milligan TJ Cunningham P Levitt (1991) ArticleTitleDifferential immunochemical markers reveal the normal distribution of brain macrophages and microglia in the developing rat brain J Comp Neurol 314 125–135

    Google Scholar 

  • H Yasuda Y Miyata (1988) ArticleTitleEnhancement of Ia synaptic transmission following muscle nerve section: dependence upon protein synthesis Neurosci Res 5 338–346

    Google Scholar 

  • SH Oliet R Piet DA Poulain (2001) ArticleTitleControl of glutamate clearance and synaptic efficacy by glial coverage of neurons Science 292 923–926

    Google Scholar 

  • FW Pfrieger BA Barres (1997) ArticleTitleSynaptic efficacy enhanced by glial cells in vitro Science 277 1684–1687

    Google Scholar 

  • AF Pitts MW Miller (2000) ArticleTitleExpression of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 in the somatosensory cortex of the mature rat: coexpression with high-affinity neurotrophin receptors J Comp Neurol 418 241–254

    Google Scholar 

  • GS Pollock E Vernon ME Forbes Q Yan YT Ma T Hsieh R Robichon DO Frost JE Johnson (2001) ArticleTitleEffects of early visual experience and diurnal rhythms on BDNF mRNA and protein levels in the visual system, hippocampus, and cerebellum. J Neurosci 21 3923–3931

    Google Scholar 

  • G Raivich GW Kreutzberg (1987) ArticleTitleThe localization and distribution of high affinity beta-nerve growth factor binding sites in the central nervous system of the adult rat. A light microscopic autoradiographic study using [125I]beta-nerve growth factor. Neuroscience 20 23–36

    Google Scholar 

  • PM Richardson VM Issa RJ Riopelle (1986) ArticleTitleDistribution of neuronal receptors for nerve growth factor in the rat. J Neurosci 6 2312–2321

    Google Scholar 

  • IA Scarisbrick PJ Isackson AJ Windebank (1999) ArticleTitleDifferential expression of brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the adult rat spinal cord: regulation by the glutamate receptor agonist kainic acid. J Neurosci 19 7757–7769

    Google Scholar 

  • GC Schatteman L Gibbs AA Lanahan P Claude M Bothwell (1988) ArticleTitleExpression of NGF receptor in the developing and adult primate central nervous system. J Neurosci 8 860–873

    Google Scholar 

  • EM Schuman (1999) ArticleTitleNeurotrophin regulation of synaptic transmission. Curr Opin Neurobiol 9 105–109

    Google Scholar 

  • A Schutte Q Yan P Mestres KM Giehl (2000) ArticleTitleThe endogenous survival promotion of axotomized rat corticospinal neurons by brain-derived neurotrophic factor is mediated via paracrine, rather than autocrine mechanisms. Neurosci Lett 290 185–188

    Google Scholar 

  • KL Seburn TC Cope (1998) ArticleTitleShort-term afferent axotomy increases both strength and depression at Ia-motoneuron synapses in Rat. J Neurosci 18 1142–1147

    Google Scholar 

  • E Sermasi E Margotti A Cattaneo L Domenici (2000) ArticleTitleTrk B signalling controls LTP but not LTD expression in the developing rat visual cortex. Eur J Neurosci 12 1411–1419

    Google Scholar 

  • DL Shelton LF Reichardt (1986) ArticleTitleStudies on the expression of the beta nerve growth factor (NGF) gene in the central nervous system: level and regional distribution of NGF mRNA suggest that NGF functions as a trophic factor for several distinct populations of neurons. Proc Natl Acad Sci USA 83 2714–2718

    Google Scholar 

  • DM Snow V Lemmon DA Carrino AL Caplan J Silver (1990) ArticleTitleSulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp Neurol 109 111–130

    Google Scholar 

  • M Taniuchi JB Schweitzer EM Johnson SuffixJr (1983) ArticleTitleNerve growth factor receptor molecules in rat brain. Proc Natl Acad Sci USA 83 1950–1954

    Google Scholar 

  • L Tessarollo KS Vogel ME Palko SW Reid LF Parada (1994) ArticleTitleTargeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons. Proc Natl Acad Sci USA 91 11844–11848

    Google Scholar 

  • EM Ullian SK Sapperstein KS Christopherson BA Barres (2001) ArticleTitleControl of synapse number by glia. Science 291 657–661

    Google Scholar 

  • DM Weisenhorn J Roback AN Young BH Wainer (1999) ArticleTitleCellular aspects of trophic actions in the nervous system Int Rev Cytol 189 177–265

    Google Scholar 

  • P Wenner MJ O’Donovan MP Matise (2000) ArticleTitleTopographical and physiological characterization of interneurons that express engrailed-1 in the embryonic chick spinal cord. J Neurophysiol 84 2651–2657

    Google Scholar 

  • J Widenfalk K Lundstromer M Jubran S Brene L Olson (2001) ArticleTitleNeurotrophic Factors and Receptors in the Immature and Adult Spinal Cord after Mechanical Injury or Kainic Acid J Neurosci 21 3457–3475

    Google Scholar 

  • M Yamamoto G Sobue K Yamamoto S Terao T Mitsuma (1996) ArticleTitleExpression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues Neurochem Res 21 929–938

    Google Scholar 

  • S Zhang C Zettler EJ Cupler P Hurtado K Wong RA Rush (2000) ArticleTitleNeurotrophin 4/5 immunoassay: identification of sources of errors for the quantification of neurotrophins J Neurosci Methods 99 119–127

    Google Scholar 

  • SH Zhang XF Zhou RA Rush (1999) ArticleTitleMeasurement of neurotrophin 4/5 in rat tissues by a sensitive immunoassay J Neurosci Methods 89 69–74

    Google Scholar 

  • SH Zhang XF Zhou RA Rush (2001) ArticleTitleExtraction and quantification of the neurotrophins Methods Mol Biol 169 31–41

    Google Scholar 

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Riley, C.P., Cope, T.C. & Buck, C.R. CNS neurotrophins are biologically active and expressed by multiple cell types. J Mol Hist 35, 771–783 (2004). https://doi.org/10.1007/s10735-004-0778-9

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