Tissue Localization of Nerve Growth Factor and Nerve Growth Factor Receptors

  • M. Bothwell
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 165)


The pioneering investigations of Levi-Montalcini and coworkers established that nerve growth factor (NGF) is an important physiological regulator of neurons of the peripheral nervous system. No doubt in part because of the dramatic and specific effects on the sympathetic and sensory nervous system resulting from immunochemically depriving rodents of NGF (Levi-Montalcini and Booker 1960; Johnson et al. 1983), the notion that the action of NGF was directed exclusively to these peripheral neurons became firmly entrenched. A functional model which proposed that NGF was produced by targets of sensory and sympathetic innervation, regulating the specificity of axon growth to the target and the survival of neurons which found the correct target, became dogmatically accepted. Over the last few years it has become clear that these concepts are only partially correct. Aided in substantial part by improved methods for characterization of sites of expression of NGF and its receptor, it has been shown that the biology of NGF action is much more complicated than was initially imagined.


Nerve Growth Factor Schwann Cell Basal Forebrain Nerve Growth Factor Receptor Nerve Growth Factor mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allendoerfer KL, Shelton DL, Shooter EM, Shatz CJ (1990) Nerve growth factor receptor immunoreactivity is transiently associated with the subplate neurons of the mammalian cerebral cortex. Proc Natl Acad Sci USA 87: 187–190PubMedCrossRefGoogle Scholar
  2. Aloe L (1988) The effect of nerve growth factor and its antibody on mast cells in vivo. J Neuroimmunol 18: 1–12PubMedCrossRefGoogle Scholar
  3. Ayer-Le Lievre C, Ebendal T, Olson L, Seiger A (1983) Localization of nerve growth factor-like immunoreactivity in rat nervous tissue. Med Biol 61: 296–304Google Scholar
  4. Ayer-LeLievre C, Olson L, Ebendal T, Hallbook F, Persson H (1988a) Nerve growth factor mRNA and protein in the testis and epididymis of mouse and rat. Proc Natl Acad Sci USA 85: 2628–2632PubMedCrossRefGoogle Scholar
  5. Ayer-LeLievre C, Olson L, Ebendal T, Seiger A, Persson H (1988b) Expression of the beta-nerve growth factor gene in hippocampal neurons. Science 240: 1339–1341PubMedCrossRefGoogle Scholar
  6. Batchelor PE, Armstrong DM, Blaker SM, Gage FH (1989) Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain: response to fimbria-fornix transection. J Comp Neurol 284: 187–204PubMedCrossRefGoogle Scholar
  7. Bernd P (1985) Appearance of nerve growth factor receptors on cultured neural crest cells. Dev Biol 112: 145–156PubMedCrossRefGoogle Scholar
  8. Bernd P, Represa J (1989) Characterization and localization of nerve growth factor receptors in the embryonic otic vesicle and cochleovestibular ganglion. Dev Biol 134: 11–20PubMedCrossRefGoogle Scholar
  9. Buck CR, Martinez HJ, Black IB, Chao MV (1987) Developmentally regulated expression of the nerve growth factor receptor gene in the periphery and brain. Proc Natl Acad Sci USA 84: 3060–3063PubMedCrossRefGoogle Scholar
  10. Byers MR, Schatteman GC, Bothwell M (1990) Multiple functions of nerve growth factor receptor in developing, aging and injured rat teeth. Development 109: 461–471PubMedGoogle Scholar
  11. Carmignoto G, Maffei L, Candeo P, Canella R, Comelli C (1989) Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci 9: 1263–1272PubMedGoogle Scholar
  12. Chandler CE, Parsons LM, Hosang M, Shooter EM (1984) A monoclonal antibody modulates the interaction of nerve growth factor with PC12 cells. J Biol Chem 259: 6882–6889PubMedGoogle Scholar
  13. Chesa PG, Wolfgang JR, Thomson TM, Old LJ, Melamed MR (1988) Immunohistochemical analysis of nerve growth factor receptor expression in normal and malignant human tissues. J Histochem Cytochem 36: 383–389PubMedCrossRefGoogle Scholar
  14. Clegg DO, Large TH, Bodary SC, Reichardt LF (1989) Regulation of nerve growth factor mRNA levels in developing rat heart ventricle is not altered by sympathectomy. Dev Biol 134: 30–7PubMedCrossRefGoogle Scholar
  15. Dal Toso R, De Bernardi MA, Brooker G, Costa E, Mocchetti I (1988) Beta adrenergic and prostaglandin receptor activation increases nerve growth factor mRNA content in C6–2B rat astrocytoma cells. J Pharmacol Exp Ther 246: 1190–1193Google Scholar
  16. Davies AM, Bandtlow C, Heumann R, Korsching S, Rohrer H, Thoenen H (1987) Timing and site of nerve growth factor synthesis in developing skin in relation to innervation and expression of the receptor. Nature 326: 353–357PubMedCrossRefGoogle Scholar
  17. Dawbarn D, Allen S.1, Semenenko FM (1988a) Immunohistochemical localization of beta-nerve growth factor receptors in the forebrain of the rat. Brain Res 440: 185–189PubMedCrossRefGoogle Scholar
  18. Dawbarn D, Allen SJ, Semenenko FM (1988b) Coexistence of choline acetyltransferase and nerve growth factor receptors in the rat basal forebrain. Neurosci Lett 94: 138–144PubMedCrossRefGoogle Scholar
  19. Despres G, Giry N, Romand R (1988) Immunohistochemical localization of nerve growth factor-like protein in the organ of Corti of the developing rat. Neurosci Lett 85: 5–8PubMedCrossRefGoogle Scholar
  20. Dreyfus CF, Bernd P, Martinez HJ, Rubin SJ, Black IB (1989) GABAergic and cholinergic neurons exhibit high-affinity nerve growth factor binding in rat basal forebrain. Exp Neurol 104: 181–185PubMedCrossRefGoogle Scholar
  21. Ebendal T, Larhammar D, Persson H (1986) Structure and expression of the chicken beta nerve growth factor gene. EMBO J 5: 1483–1487PubMedGoogle Scholar
  22. Eckenstein F (1988) Transient expression of NGF-receptor-like immunoreactivity in postnatal rat brain and spinal cord. Brain Res 446: 149–154PubMedCrossRefGoogle Scholar
  23. Ernfors P, Hallbook F, Ebendal T, Shooter EM, Radeka MJ, Misko TP, Persson H (1988) Developmental and regional expression of beta-nerve growth factor receptor mRNA in the chick and rat. Neuron 1: 983–996PubMedCrossRefGoogle Scholar
  24. Ernfors P, Henschen A, Olson L, Persson H (1989) Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2: 1605–1613PubMedCrossRefGoogle Scholar
  25. Furukawa Y, Tomioka N, Sato W, Satoyoshi E (1989) Catecholamines increase nerve growth factor mRNA content in both mouse astroglial cells and fibroblast cells. FEBS Lett 247: 463–467PubMedCrossRefGoogle Scholar
  26. Gall CM, Isackson PJ (1989) Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245: 758–761PubMedCrossRefGoogle Scholar
  27. Gasser UE, Weskamp G, Otten U, Dravid AR (1986) Time course of elevation of nerve growth factor ( NGF) content in hippocampus and septum following lesions of septohippocampal pathway in rats. Brain Res 376: 351–356PubMedCrossRefGoogle Scholar
  28. Goedert M (1989) Molecular cloning of the chicken nerve growth factor gene: mRNA distribution in developing and adult tissues. Biochem Biophys Res Commun 141: 1116–1122CrossRefGoogle Scholar
  29. Green SH, Greene LA (1986) A single Mr 103,000 125I-beta-nerve growth factor affinity-labeled species represents both the low and high affinity forms of the nerve growth factor receptor. J Biol Chem 261: 15316–16326PubMedGoogle Scholar
  30. Heaton MB (1987) Influence of nerve growth factor on chick trigeminal motor nuclei explants. J Comp Neurol 265: 362–366PubMedCrossRefGoogle Scholar
  31. Hefti F, Mash DC (1989) Localization of nerve growth factor receptors in the normal human brain and in Alzheimer’s disease. Neurobiol Aging 10: 75–87PubMedCrossRefGoogle Scholar
  32. Hefti F, Hartikka J, Salvatierra WJ, Weiner WJ, Mash D (1986) Localization of nerve growth factor receptors in cholinergic neurons of the human basal forebrain. Neurosci Lett 69: 37–41PubMedCrossRefGoogle Scholar
  33. Heinrich G, Meyer TE (1988) Nerve growth factor (NGF) is present in human placenta and semen but undetectable in normal and Paget’s disease blood: measurements with an anti-mouse-NGF enzyme immunoassay using a recombinant human NGF reference. Biochem Biophys Res Commun 155: 482–486PubMedCrossRefGoogle Scholar
  34. Hellweg R, Bandtlow CE, Heumann R, Korsching S (1988) Nerve growth factor synthesis in cultured rat iris: modulation by endogenous transmitter substances. Exp Cell Res 179: 18–30PubMedCrossRefGoogle Scholar
  35. Hempstead BL, Schlierer LS, Chao MV (1989) Expression of functional nerve growth factor receptors after gene transfer. Science 243: 373–375PubMedCrossRefGoogle Scholar
  36. Heuer JG, Fatemie-Nainie S, Wheeler EW, Bothwell M (1990) Structure and developmental expression of the chicken NGF receptor. Dev Biol 137: 287–304PubMedCrossRefGoogle Scholar
  37. Heumann R, Korsching S, Scott J, Thoenen H (1984) Relationship between levels of nerve growth factor ( NGF) and its mRNA in sympathetic ganglia and peripheral target tissues. EMBO J 3: 3183–3189PubMedGoogle Scholar
  38. Heumann R, Lindholm D, Bandtlow C, Meyer M, Radeke MJ, Misko TP, Shooter E, Thoenen 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: 8735–8739PubMedCrossRefGoogle Scholar
  39. Houlgate T, Wion D, Brachet P (1989) Levels of nerve growth factor secreted by rat primary fibroblasts and iris transplants are influenced by serum and glucocorticodis. Dev Brain Res 47: 171–179CrossRefGoogle Scholar
  40. Johnson EM Jr, Osborne PA, Rydel RE, Schmidt RE, Pearson J (1983) Characterization of the effects of autoimmune nerve growth factor deprivation in the developing guinea pig. Neuroscience 8: 631–642PubMedCrossRefGoogle Scholar
  41. Koo PH, Stach RW (1989) Interaction of nerve growth factor with murine alpha-macroglobulin. J Neurosci Res 22: 247–261PubMedCrossRefGoogle Scholar
  42. Koh S, Oyler GA, Higgins GA (1989) Localization of nerve growth factor receptor mRNA and protein in adult rat brain. Exp Neurol 106: 209–221PubMedCrossRefGoogle Scholar
  43. Kordower JH, Bartus RT, Bothwell M, Schatteman GC, Gash DM (1988) Nerve growth factor receptor immunoreactivity in the nonhuman primate (Cebus apella): distribution, morphology and colocalization with cholinergie enzymes. J Comp Neurol 277: 465–486PubMedCrossRefGoogle Scholar
  44. Korsching S, Thoenen H (1983) Nerve growth factor in sympathetic ganglia and corresponding target organs in the rat:correlation with density of innervation. Proc Natl Acad Sci USA 80: 3513–3516PubMedCrossRefGoogle Scholar
  45. Korsching S, Thoenen H (1988) Developmental changes of nerve growth factor levels in sympathetic ganglia and their target organs. Dev Biol 126: 40–46PubMedCrossRefGoogle Scholar
  46. Korsching S, Auburger G, Heumann R, Scott J, Thoenen H (1985) Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation. EMBO J 4: 1389–1393PubMedGoogle Scholar
  47. Lahtinen T, Soinila S, Lakshmanan J (1989) Biological demonstration of nerve growth factor in the rat pituitary gland. Neuroscience 30: 165–170PubMedCrossRefGoogle Scholar
  48. Large TH, Bodary SC, Clegg DO, Weskamp G, Otten U, Reichardt LF (1986) Nerve growth factor gene expression in the developing rat brain. Science 234: 352–355PubMedCrossRefGoogle Scholar
  49. Large TH, Weskamp G, Helder JC, Radeke MJ, Misko TO, Shooter EM, Reichardt L (1989) Structure and developmental expression of the nerve growth factor receptor in the chicken central nervous system. Neuron 2: 1123–1134PubMedCrossRefGoogle Scholar
  50. Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H and Barde Y-A (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341: 149–154PubMedCrossRefGoogle Scholar
  51. Lemke G, Chao MV (1988) Axons regulate Schwann cell expression of the major myelin and nerve growth factor receptor genes. Development 102: 499–504PubMedGoogle Scholar
  52. Levi-Montalcini R, Booker B (1960) Destruction of the sympathetic ganglia in mammals by an antiserum to NGF. Proc Natl Acad Sci USA 46: 384–391PubMedCrossRefGoogle Scholar
  53. Lindholm D, Heumann R, Meyer M, Thoenen H (1987) Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 330: 658–659PubMedCrossRefGoogle Scholar
  54. Lindholm D, Heumann R, Hengerer B, Thoenen H (1988) Interleukin 1 increases stability and transcription of mRNA encoding nerve growth factor in cultured rat fibroblasts. J Biol Chem 263: 16348–16351PubMedGoogle Scholar
  55. Lindsay RM (1979) Adult rat brain astrocytes support survival of both NGF-dependent and NGFindependent neurons. Nature 282: 80–82PubMedCrossRefGoogle Scholar
  56. Lorez H, Keller F, Ruess G, Otten U (1989) Nerve growth factor increases in adult rat brain after hypoxic injury. Neurosci Lett 10: 339–344CrossRefGoogle Scholar
  57. Lu B, Buck CR, Dreyfus CF, Black IB (1989) Expression of NGF and NGF receptor mRNAs in the developing brain: evidence for local delivery and action of NGF. Exp Neurol 104: 191–199PubMedCrossRefGoogle Scholar
  58. Mallat M, Houlgatte R, Brachet P, Prochiantz A (1989) Lipopolysaccharide-stimulated rat brain macrophages release NGF in vitro. Devi Biol 133: 309–311CrossRefGoogle Scholar
  59. Marano N, Dietzschold B, Earley JJ Jr, Schatteman GC, Thompson S, Grob P, Ross AH, Bothwell M, Atkinson BF, Koprowski H (1987) Purification and amino terminal sequencing of human melanoma nerve growth factor receptor. J Neurochem 48: 225–232PubMedCrossRefGoogle Scholar
  60. Matsuda H, Coughlin MD, Bienenstock J, Denburg JA (1988) Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci USA 85: 6508–6512PubMedCrossRefGoogle Scholar
  61. Mocchetti I, De Bernardi MA, Szekely AM, Alho H (1989) Regulation of nerve growth factor biosynthesis by beta-adrenergic receptor activation in astrocytoma cells: a potential role of c-fos protein. Proc Natl Acad Sci USA 86: 3891–3895PubMedCrossRefGoogle Scholar
  62. Mokuno K, Sobue G, Reddy UR, Wurzer J (1988) Regulation of Schwann cell nerve growth factor receptor by cyclic adenosine 3’,5’-monophosphate. J Neurosci Res 21: 465–472PubMedCrossRefGoogle Scholar
  63. Morgan B, Thorpe LW, Marchetti D, Perez-Polo JR (1989) Expression of nerve growth factor receptors by human peripheral blood mononuclear cells. J Neurosci Res 23: 41–45PubMedCrossRefGoogle Scholar
  64. Mufson EJ, Bothwell M, Hersh LB, Kordower JH (1989) Nerve growth factor receptor immunoreactive profiles in the normal, aged human basal forebrain: colocalization with cholinergic neurons. J Comp Neurol 285: 196–217PubMedCrossRefGoogle Scholar
  65. Patterson SL, Bothwell M (1989) NGF in choroid plexus and CSF. Soc Neurosci Abstr 15: 868Google Scholar
  66. Pearson J, Johnson EM, Brandler L (1983) Effects of antibodies to nerve growth factor on intrauterine development of derivatives of cranial neural crest and placode in the guinea pig. Dev Biol 96: 32–36PubMedCrossRefGoogle Scholar
  67. Pioro EP, Cuello AC (1988) Purkinje cells of adult rat cerebellum express nerve growth factor receptor immunoreactivity: light microscopic observations. Brain Res 455: 182–186PubMedCrossRefGoogle Scholar
  68. Raivich G, Kreutzberg GW (1987) The 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: 23–36PubMedCrossRefGoogle Scholar
  69. Raivich G, Zimmerman A, Sutter A (1985) The spatial and temporal pattern of beta NGF receptor expression in the developing chick embryo. EMBO J 4: 637–644PubMedGoogle Scholar
  70. Raivich G, Zimmerman A, Sutter A (1987) Nerve growth factor ( NGF) receptor expression in chicken cranial development. J Comp Neurol 256: 229–245PubMedCrossRefGoogle Scholar
  71. Represa J, Brend P (1989) Nerve growth factor and serum differentially regulate development of the embryonic otic vesicle and cochleovestibular ganglion in vitro. Dev Biol 134: 21–29PubMedCrossRefGoogle Scholar
  72. Richardson PM, Riopelle RJ (1984) Uptake of nerve growth factor along peripheral and spinal axons of primary sensory neurons. J Neurosci 4: 1683–1689PubMedGoogle Scholar
  73. Shelton DL, Reichardt LF (1984) Expression of the beta-nerve growth factor gene correlates with the density of sympathetic innervation of effector organs. Proc Natl Acad Sci USA 81: 7951–7955PubMedCrossRefGoogle Scholar
  74. Shelton DL, Reichardt LF (1986) Studies 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 atrophic factor for several distinct populations of neurons. Proc Natl Acad Sci USA 83: 2714–2718PubMedCrossRefGoogle Scholar
  75. Soinila S, Lakshmanan J, Lahtinen T (1988) Nerve growth factor-like activity in the rat pituitary intermediate lobe. Neurosci Res 6: 123–130PubMedCrossRefGoogle Scholar
  76. Springer JE, Koh S, Tayrien MW, Loy R (1987) Basal forebrain magnocellular neurons stain for nerve growth factor receptor: correlation with cholinergic cell bodies and effects of axotomy. J Neurosci Res 17: 111–118PubMedCrossRefGoogle Scholar
  77. Stoekel K, Thoenen H (1975) Retrograde transport of nerve growth factor: specificity and biological importance. Brain Res 85: 337–341CrossRefGoogle Scholar
  78. Suda K, Barde YA, Thoenen H (1978) Nerve growth factor in mouse and rat serum: Correlation between bioassay and radioimmunoassay determination. Proc Natl Acad Sci USA 75: 4042–4046PubMedCrossRefGoogle Scholar
  79. Taniuchi M, Clark HB, Johnson EM Jr (1986) Induction of nerve growth factor receptors in Schwann cells after axotomy. Proc Natl Acad USA 83: 4094–4098CrossRefGoogle Scholar
  80. Thomson TM, Rettig WJ, Chesa PG, Green SH, Mena AC, Old LJ (1988) Expression of human nerve growth factor receptor on cells derived from all three germ layers. Exp Cell Res 174: 533–539PubMedCrossRefGoogle Scholar
  81. Thompson S, Schatteman GC, Gown AM, Bothwell M (1989) A monoclonal antibody against nerve growth factor receptor: immunohistochemical analysis of normal and neoplastic human tissue. Am J Clin Path 92: 415–423PubMedGoogle Scholar
  82. Thorpe LW, Perez-Polo JR (1987) The influence of nerve growth factor on the in vitro proliferative response of rat spleen lymphocytes. J Neurosci Res 18: 134–139PubMedCrossRefGoogle Scholar
  83. Tomioka M, Stead RH, Nielsen L, Coughlin MD, Bienenstock J (1988) Nerve growth factor enhances antigen and other secretagogue-induced histamine release from rat peritoneal mast cells in the absence of phosphatidylserine. J Allergy Clin Immunol 82: 599–607PubMedCrossRefGoogle Scholar
  84. Turner JE, Glaze KA (1977) Regenerative repair in the severed optic nerve of the newt: effect of nerve growth factor. Exp Neurol 57: 687–697PubMedCrossRefGoogle Scholar
  85. Verge VM, Riopelle RJ, Richardson PM (1989) Nerve growth factor receptors on normal and injured sensory neurons. J Neurosci 9: 914–922PubMedGoogle Scholar
  86. Vickland H, Kott JN, Westrum LE, Patterson SL, Bothwell M (1989) Electron microscopy shows NGF receptor labelling of glial-like cells in olfactory bulb. Soc Neurosci Abstr 15: 868Google Scholar
  87. Whittemore SR, Ebendal T, Larkfors L, Olson L, Seiger A, Stromberg I, Persson H (1986) Developmental and regional expression of beta nerve growth factor messenger RNA and protein in the rat central nervous system. Proc Natl Acad Sci USA 83: 817–821PubMedCrossRefGoogle Scholar
  88. Whittemore SR, Friedman PL, Larhammar D, Persson H, Ebendal T (1988) Rat beta-nerve growth factor sequence and site of synthesis in the adult hippocampus. J Neurosci Res 20: 403–410PubMedCrossRefGoogle Scholar
  89. Yan Q, Johnson EM (1988) An immunohistochemical study of the nerve growth factor receptor in developing rats. J Neurosci 8: 3481–3498PubMedGoogle Scholar
  90. Yip HK, Johnson EM (1984) Developing dorsal root ganglionic neurons require trophic support from their central processes: evidence for a role of retrogradely transported nerve growth factor from the central nervous system to the periphery. Proc Natl Acad Sci USA 81: 6245–6249PubMedCrossRefGoogle Scholar
  91. Zimmerman A, Sutter A (1983) Beta nerve growth factor (beta-NGF) receptors on glial cells. Cell—cell interaction between neurones and Schwann cells in cultures of chick sensory ganglia. EMBO J 2: 879–885Google Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1991

Authors and Affiliations

  • M. Bothwell
    • 1
  1. 1.Department of Physiology & Biophysics, School of MedicineUniversity of WashingtonSeattleUSA

Personalised recommendations