Molecular Neurobiology

, Volume 21, Issue 3, pp 109–135 | Cite as

Regulation of neurotrophin signaling in aging sensory and motoneurons

Dissipation of target support?
  • Brun Ulfhake
  • Esbjorn Bergman
  • Erik Edström
  • Bengt T. Fundin
  • Hans Johnson
  • Susanna Kullberg
  • Yu Ming


A hallmark of senescence is sensorimotor impairment, involving locomotion and postural control as well as fine-tuned movements. Sensory and motoneurons are not lost to any significant degree with advancing age, but do show characteristic changes in gene-expression pattern, morphology, and connectivity. This review covers recent experimental findings corroborating that alterations in trophic signaling may induce several of the phenotypic changes seen in primary sensory and motoneurons during aging. Furthermore, the data suggests that target failure, and/or breakdown of neuron-target interaction, is a critical event in the aging process of sensory and motoneurons.

Index Entries

Aging glial cell line-derived neurotrophic factor nerve growth factor brain-derived neurotrophic factor neurotrophin-3 neurotrophin-4 trk receptor p75NTR ret GFR 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Woollacott M. H. (1986) Gait and postural control in the aging adult, in Disorders of Posture and Gait (Bles W. and Brandt T., eds.), Elsevier Science Publishers B. V., Amsterdam, pp. 325–336.Google Scholar
  2. 2.
    Larish D. D., Martin P. E., and Mungiole M. (1988) Characteristic patterns of gait in the healthy old, in Central Determinants of Age-Related Declines in Motor Function (Joseph J. A., eds.), The New York Academy of Sciences, New York, pp. 18–32.Google Scholar
  3. 3.
    Lamberts S. W. J., van den Beld A. W., and van der Lely A. J. (1997) The endocrinology of aging. Science 278, 419–424.PubMedGoogle Scholar
  4. 4.
    Larsson L. (1982) Aging in mammalian skeletal muscle, in The Aging Motor System (Mortimer J. A., Pirozzolo F. J. and Maletta G. J., eds.), Praeger, New York, pp. 61–97.Google Scholar
  5. 5.
    Brocklehurst J. C., Robertson D., and James-Groom P. (1982) Clinical correlates of sway in old age-sensory modalities. Age Aging 11, 1–10.Google Scholar
  6. 6.
    Dyck P. J., Karnes J., O’Brien P. C., and Zimmerman I. (1984) Detection thresholds of cutaneous sensations in humans, in Peripheral Neuropathy (Dyck P. J., Thomas P. K., Lambert E. H., and Bunge R., eds.), Saunders, Philadelphia, pp. 1103–1138.Google Scholar
  7. 7.
    Schmidt R. F., Wahren L. K., and Hagbarth K. E. (1990) Multiunit neural responses to strong finger pulp vibration. I. Relationship to age. Acta Phys. Scand. 140, 1–10.Google Scholar
  8. 8.
    Ferrell W. R., Crighton A., and Sturrock R. D. (1992) Age-dependent changes in position sense in human proximal interphalangeal joints. Neuroreport 3, 259–61.PubMedGoogle Scholar
  9. 9.
    de Neeling J. N., Beks P. J., Bertelsmann F. W., Heine R. J., and Bouter L. M. (1994) Sensory thresholds in older adults: reproducibility and reference values. Muscle Nerve 17, 454–61.PubMedGoogle Scholar
  10. 10.
    Gescheider G. A., Bolanowski S. J., Hall K. L., Hoffman K. E., and Verrillo R. T. (1994) The effects of aging on information-processing channels in the sense of touch: I. Absolute sensitivity. Somatosens. Mot. Res. 11, 345–57.PubMedGoogle Scholar
  11. 11.
    Quoniam C., Hay L., Roll J. P., and Harlay F. (1995) Age effects on reflex and postural responses to propriomuscular inputs generated by tendon vibration. J. Gerontol. Series A, Biol. Sci. Med. Sci. 50, B155–65.Google Scholar
  12. 12.
    Kokmen E., Bossemeyer R. W., Jr., Barney J., and Williams W. J. (1977) Neurological manifestations of aging. J. Gerontol. 32, 411–9.PubMedGoogle Scholar
  13. 13.
    Whanger A. D. and Wang H. S. (1974) Clinical correlates of the vibratory sense in elderly psychiatric patients. J. Gerontol. 29, 39–45.PubMedGoogle Scholar
  14. 14.
    Khalil Z., Ralevic V., Bassirat M., Dusting G. J., and Helme R. D. (1994) Effects of ageing on sensory nerve function in rat skin. Brain Res. 641, 265–72.PubMedGoogle Scholar
  15. 15.
    Cowen T. and Thrasivoulou C. (1990) Cerebrovascular nerves in old rats show reduced accumulation of 5-hydroxytryptamine and loss of nerve fibres. Brain Res. 513, 237–243.PubMedGoogle Scholar
  16. 16.
    Abdel-Rahman T. A. and Cowen T. (1993) Neurodegeneration in sweat glands and skin of aged rats. J. Auton. Nerv. Syst. 46, 55–63.Google Scholar
  17. 17.
    Cauna N. (1965) The effects of aging on the receptor organs of the human dermis, in Advances in Biology of the Skin (Montagna, W., eds), Pergamon Press, New York, pp. 63–96.Google Scholar
  18. 18.
    Gescheider G. A., Valetutti A. A., Jr., Padula M. C., and Verrillo R. T. (1992) Vibrotactile forward masking as a function of age. J. Acoust. Soc. Am. 91, 1690–1696.PubMedGoogle Scholar
  19. 19.
    Macintosh S. R. and Sinclair D. C. (1978) Agerelated changes in the innervation of the rat snout. J. Anat. 125, 149–154.PubMedGoogle Scholar
  20. 20.
    Cowen T., Haven A. J., Wen Qin C., Gallen D. D., Franc F., and Burnstock G. (1982) Development and ageing of perivascular adrenergic nerves in the rabbit. A quantitative fluorescence histochemical study using image analysis. J. Auton. Nerv. Syst. 5, 317–336.PubMedGoogle Scholar
  21. 21.
    Dhall U., Cowen T., Haven A. J., and Burnstock G. (1986) Perivascular noradrenergic and peptide-containing nerves show different patterns of change during development and ageing in the guinea-pig. J. Auton. Nerv. Syst. 16, 109–126.PubMedGoogle Scholar
  22. 22.
    Mione M. C., Dhital K. K., Amenta F., and Burnstock G. (1988) An increase in the expression of neuropeptidergic vasodilator, but not vasoconstrictor, cerebrovascular nerves in aging rats. Brain Res. 460, 103–113.PubMedGoogle Scholar
  23. 23.
    Navarro X. and Kennedy W. R. (1990) Changes in sudomotor nerve territories with aging in the mouse. J. Auton. Nerv. Syst. 31, 101–107.PubMedGoogle Scholar
  24. 24.
    Fundin B. T., Bergman E., and Ulfhake B. (1997) Alterations in mystacial pad innervation in the aged rat. Exp. Brain Res. 117, 324–340.PubMedGoogle Scholar
  25. 25.
    Khalil Z. and Helme R. (1996) Sensory peptides as neuromodulators of wound healing in aged rats. J. Gerontol. Series A, Biol. Sci. Med. Sci. 51, B354–61.Google Scholar
  26. 26.
    Makinodan T. and Kay M. M. B. (1989) Age influence on the immune system. Adv. Immunol. 29, 287–330.Google Scholar
  27. 27.
    Parkhouse N. and LeQuesne P. M. (1988) Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions. New Engl. J. Med. 318, 1306–1309.PubMedCrossRefGoogle Scholar
  28. 28.
    Gutman B. and Hanzlikova V. (1972) Age changes in the neuromuscular system. Scientechnica Ltd., Bristol: Scientechnica, 1–20.Google Scholar
  29. 29.
    Larsson L. (1995) Motor units: remodeling in aged rats. J. Gerontol. 50A, 91–95.Google Scholar
  30. 30.
    Ansved T. and Larsson L. (1990) Quantitative and qualitative morphological properties of the soleus motor nerve and the L5 ventral root in young and old rats. J. Neurol. Sci. 96, 269–282.PubMedGoogle Scholar
  31. 31.
    Fujisawa K. (1974) Some observations on the skeletal musculature of aged rats. J. Neurol. Sci. 22, 353–366.PubMedGoogle Scholar
  32. 32.
    Tomonaga M. (1977) Histochemical and ultrastructural changes in senile human skeletal muscle. J. Am. Geriatr. Soc. 25, 125–131.PubMedGoogle Scholar
  33. 33.
    Caccia M. R., Harris J. B., and Johnson M. A. (1979) Morphology and physiology of skeletal muscle in aging rodents. Muscle Nerve 2, 202–212.PubMedGoogle Scholar
  34. 34.
    Satorre J., Cano J., and Reinoso-Suarez F. (1985) Stability of the neuronal population of the dorsal lateral geniculate nucleus (LGNd) of aged rats. Brain Res 339, 375–377.PubMedGoogle Scholar
  35. 35.
    Coleman P. D. and Flood D. G. (1987) Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol. Aging 8, 521–545.PubMedGoogle Scholar
  36. 36.
    Ahmad A. and Spear P. D. (1993) Effects of aging on the size, density, and number of rhesus monkey lateral geniculate neurons. J. Comp. Neurol. 334, 631–643.PubMedGoogle Scholar
  37. 37.
    Monji A., Morimoto N., Okuyama I., Umeno K., Nagatsu I., Ibata Y., and Tashiro N. (1994) The number of noradrenergic and adrenergic neurons in the brain stem does not change with age in male Sprague-Dawley rats. Brain Research 641, 171–175.PubMedGoogle Scholar
  38. 38.
    Madeira M. D., Sousa N., Santer R. M., Paula-Barbosa M. M., and Gundersen H. J. (1995) Age and sex do not affect the volume, cell numbers, or cell size of the suprachiasmatic nucleus of the rat: an unbiased stereological study. J. Comp. Neurol. 361, 585–601.PubMedGoogle Scholar
  39. 39.
    Wickelgren I. (1996) Is hippocampal cell death a myth? [news] [see comments]. Science 271, 1229–1230.PubMedGoogle Scholar
  40. 40.
    Morrison J. H. and Hof P. J. (1997) Life and death of neurons in the aging brain. Science 278, 412–419.PubMedGoogle Scholar
  41. 41.
    Ohta M., Offord K., and Dyck P. J. (1974) Morphometric evaluation of first sacral ganglia of man. J. Neurol. Sci. 22, 73–82.Google Scholar
  42. 42.
    La Forte R. A., Melville S., Chung K., and Coggeshall R. E. (1991) Absence of neurogenesis of adult rat dorsal root ganglion cells [see comments]. Somatosens. Mot. Res. 8, 3–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Bergman E. and Ulfhake B. (1998) Loss of primary sensory neurons in the very old rat: Neuron number estimates using the disector method and confocal optical sectioning. J. Comp. Neurol. 396, 211–222.PubMedGoogle Scholar
  44. 44.
    Johnson H., Mossberg K., Arvidsson U., Piehl F., Hökfelt T., and Ulfhake B. (1995) Increase in alpha-CGRP and GAP-43 in aged motoneurons: a study of peptides, growth factors, and ChAT mRNA in the lumbar spinal cord of senescent rats with symptoms of hindlimb incapacities. J. Comp. Neurol. 359, 69–89.PubMedGoogle Scholar
  45. 45.
    Tomlinson B. E. and Irving D. (1977) The numbers of limb motor neurons in human lumbosacral cord throughout life. J. Neurol. Sci. 34, 213–219.PubMedGoogle Scholar
  46. 46.
    Kawamura Y. and Dyck P. J. (1977) Lumbar motoneurons of man: III. The number and diameter distribution of large- and intermediate-diameter cytons by nuclear columns. J. Neuropathol Exp. Neurol. 39, 956–963.Google Scholar
  47. 47.
    Kawamura Y., O’Brien P., Okazaki H., and Dyck P. J. (1977) Lumbar motoneurons of man: II. The number and diameter distribution of large-and intermediate-diameter cytons in motoneuron columns of spinal cord of man. J. Neuropathol. Exp. Neurol. 36, 861–870.PubMedGoogle Scholar
  48. 48.
    Bergman E., Ulfhake B., and Fundin B. T. (2000) Regulation of NGF-family ligands and receptors in adulthood and senescence: correlation to degenerative and regenerative changes in the cutaneous innervation. Eur. J. Neurosci. 12, 2694–2706.PubMedGoogle Scholar
  49. 49.
    Bergman E., Johnson H., Zhang X., Hökfelt T., and Ulfhake B. (1996) Neuropeptides and neurotrophin receptor mRNAs in primary sensory neurons of aged rats. J. Comp. Neurol. 375, 303–320.PubMedGoogle Scholar
  50. 50.
    Bergman E., Kullberg S., Ming Y., and Ulfhake B. (1999) Upregulation of GFRalpha-1 and c-ret in primary sensory neurons and spinal motoneurons of aged rats. J. Neurosci. Res. 57, 153–165.PubMedGoogle Scholar
  51. 51.
    Bergman E., Fundin B. T., and Ulfhake B. (1999) Effects of aging and axotomy on the expression of neurotrophin receptors in primary sensory neurons. J. Comp. Neurol. 410, 368–386.PubMedGoogle Scholar
  52. 52.
    Bergman E., Carlsson K., Liljeborg A., Manders E., Hökfelt T., and Ulfhake B. (1999) Neuropeptides, nitric oxide synthase and GAP-43 in B4-binding and RT97 immunoreactive primary sensory neurons: normal distribution pattern and changes after peripheral nerve transection and aging. Brain Res. 832, 63–83.PubMedGoogle Scholar
  53. 53.
    Bergman E. and Ulfhake B. (2000) Structural changes in peripheral nerves and in the central termination pattern of CTB and B4 labeled primary sensory neurons of the aged rat. Unpublished observations.Google Scholar
  54. 54.
    Ming Y., Bergman E., Edström E., and Ulfhake B. (1999) Evidence for increased GDNF signaling in aged sensory and motor neurons. NeuroReport 10, 1529–1535.PubMedGoogle Scholar
  55. 55.
    Ming Y., Bergman E., Edström E., and Ulfhake B. (1999) Reciprocal changes in the expression of neurotrophin mRNAs in target tissues and peripheral nerves of aged rats. Neurosci. Lett. 273, 187–190.PubMedGoogle Scholar
  56. 56.
    Rao R. S. and Krinke G. (1983) Changes with age in the number and size of myelinated axons in the rat L4 dorsal spinal root. Acta Anat. (Basel) 117, 187–192.Google Scholar
  57. 57.
    Parhad I. M., Scott J. N., Cellars L. A., Bains J. S., Krekoski C. A., and Clark A. W. (1995) Axonal atrophy in aging is associated with a decline in neurofilament gene expression. J. Neurosci. Res. 41, 355–66.PubMedGoogle Scholar
  58. 58.
    Kuchel G. A., Poon T., Irshad K., Richard C., Julien J. P., and Cowen T. (1996) Decreased neurofilament gene expression is an index of selective axonal hypotrophy in ageing. Neuroreport 7, 1353–1359.PubMedGoogle Scholar
  59. 59.
    Fujisawa K. (1988) Study of axonal dystrophy. III. Posterior funiculus and posterior column of ageing and old rats. Acta Neuropathol. (Berl.) 76, 115–127.Google Scholar
  60. 60.
    Knox C. A., Kokmen E., and Dyck P. J. (1989) Morphometric alteration of rat myelinated fibers with aging. J. Neuropathol. Exp. Neurol. 48, 119–139.PubMedGoogle Scholar
  61. 61.
    Dalsgaard C. J. (1988) The sensory system, in Handbook of Chemical Neuroanatomy (Björklund A., Hökfelt T., and Owman C. eds.), Elsevier Science Publishers B. V., Amsterdam, pp. 599–636.Google Scholar
  62. 62.
    Willis W. D. and Coggeshall R. E. (1991) Sensory Mechanisms of the Spinal Cord. Plenum Press, New York.Google Scholar
  63. 63.
    Lawson S. L. (1992) Morphological and biochemical cell types of sensory neurones, in Sensory Neurons: Diversity, Development, Plasticity (Scott S. A., eds.), Oxford University Press, New York, pp. 27–59.Google Scholar
  64. 64.
    Hökfelt T. (1991) Neuropeptides in perspective: the last ten years. Neuron 7, 867–879.PubMedGoogle Scholar
  65. 65.
    Hökfelt T., Zhang X., and Wiesenfeld-Hallin Z. (1994) Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci. 17, 22–30.PubMedGoogle Scholar
  66. 66.
    Lewin G. R. and Mendell L. M. (1993) Nerve growth factor and nociception. Trends Neurosci. 16, 353–359.PubMedGoogle Scholar
  67. 67.
    Lembeck F. and Holzer P. (1979) Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn-Schmeidebergs Arch. Pharmacol. 310, 175–183.Google Scholar
  68. 68.
    Brain S. D., Williams T. J., Tippins J. R., Morris H. R., and MacIntyre I. (1985) Calcitonin generelated peptide is a potent vasodilator. Nature 313, 54–56.PubMedGoogle Scholar
  69. 69.
    Louis S. M., Jamieson A., Russel N. J. W., and Dockary G. J. (1989) The role of substance P and calcitonin gene-related peptide in neurogenic plasma extravasation and vasodilation in the rat. Neuroscience 32, 581–586.PubMedGoogle Scholar
  70. 70.
    Delay-Goyet P., Satoh H., and Lundberg J. M. (1992) Relative involvement of substance P and CGRP mechanisms in antidromic vasodilation in the rat skin. Acta Physiol. Scand. 146, 537–538.PubMedCrossRefGoogle Scholar
  71. 71.
    Helme R. D. and McKernan S. (1985) Effects of age on the axon reflex response to noxious chemical stimulation. Clin. Exp. Neurol. 22, 57–62.Google Scholar
  72. 72.
    Brewster W. J., Fernyhough P., Diemel L. T., Mohiuddin L., and Tomlinson D. R. (1994) Diabetic neuropathy, nerve growth factor and other neurotrophic factors. Trends Neurosci. 17, 321–325.PubMedGoogle Scholar
  73. 73.
    Cowen T. and Gavazzi I. (1998) Plasticity in adult and ageing sympathetic neurons. Prog. Neurobiol 54, 249–288.PubMedGoogle Scholar
  74. 74.
    Rask C. A. and Escandon E. (1999) Neurotrophin treatment of peripheral sensory neuropathies., in Neurotrophic Factors (Hefti F., ed.), Springer-Verlag, Berlin, pp. 53–79.Google Scholar
  75. 75.
    Barde Y.-A. (1999) Biological roles of neurotrophins, in Neurotrophic Factors (Hefti F., ed.), Springer-Verlag, Berlin, pp. 1–31.Google Scholar
  76. 76.
    Rylett R. J. and Williams L. R. (1994) Role of neurotrophins in cholinergic-neurone function in the adult and aged CNS. Trends Neurosci. 17, 486–490.PubMedGoogle Scholar
  77. 77.
    Lindsay R. M. (1992) The role of neurotrophic factors in functional maintenance of mature sensory neurons, in Sensory neurones: Diversity, development and plasticity (Scott S. A. eds.), Oxford University Press, New York, pp. 404–420.Google Scholar
  78. 78.
    Lewin G. R. and Barde Y.-A. (1996) Physiology of the neurotrophins. Ann. Rev. Neurosci. 19, 289–317.PubMedGoogle Scholar
  79. 79.
    Kitzman P. H., Perrone T. N., LeMaster A. M., Davis B. M., and Albers K. M. (1998) Level of p75 receptor expression in sensory ganglia is modulated by NGF level in the target tissue. J. Neurobiol. 35, 258–70.PubMedGoogle Scholar
  80. 80.
    Lindsay R. M., Shooter E. M., Radeke M. J., Misko T. P., Dechant G., Thoenen H., and Lindholm D. (1990) Nerve growth factor regulates expression of the nerve growth factor receptor gene in adult sensory neurons. Eur. J. Neurosci. 2, 389–396.PubMedGoogle Scholar
  81. 81.
    Holtzman D. M., Li Y., Parada L. F., Kinsman S., Chen C. K., Valletta J. S., Zhou J., et al. (1992) p140trk mRna marks Ngf-responsive forebrain neurons: evidence that trk gene expression is induced by Ngf. Neuron 9, 465–78.PubMedGoogle Scholar
  82. 82.
    Raivich G., Hellweg R., and Kreutzberg G. W. (1991) NGF receptor-mediated reduction in axonal NGF uptake and retrograde transport following sciatic nerve injury during regeneration. Neuron 7, 151–164.PubMedGoogle Scholar
  83. 83.
    Krekoski C. A., Parhad I. M., and Clark A. W. (1996) Attenuation and recovery of nerve growth factor receptor mRNA in dorsal root ganglion neurons following axotomy. J. Neurosci. Res. 43, 1–11.PubMedGoogle Scholar
  84. 84.
    Verge V. M., Merlio J. P., Grondin J., Ernfors P., Persson H., Riopelle R. J., et al. (1992) Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF. J. Neurosci. 12, 4011–4022.PubMedGoogle Scholar
  85. 85.
    Verge V. M., Gratto K. A., Karchewski L. A., and Richardson P. M. (1996) Neurotrophins and nerve injury in the adult. Phil. Trans. Royal Soc. London — Series B: Biol. Sci. 351, 423–430.Google Scholar
  86. 86.
    Bernd P. and Greene L. A. (1984) Association of 125I-nerve growth factor with PC-12 pheochromocytoma cells. Evidence for internalization via high-affinity receptors only and for long-term regulation by nerve growth factor of high- and low- affinity receptors. J. Biol. Chem. 259, 15509–15516.PubMedGoogle Scholar
  87. 87.
    Cowen T. (1993) Ageing in the autonomic nervous system: a result of nerve-target interactions? A review. Mech. Aging Dev. 68, 163–73.PubMedGoogle Scholar
  88. 88.
    Thrasivoulou C. and Cowen T. (1995) Regulation of rat sympathetic nerve density by target tissues and NGF in maturity and old age. Eur. J. Neurosci. 7, 381–387.PubMedGoogle Scholar
  89. 89.
    Whitworth I. H., Terenghi G., Green C. J., Brown R. A., Stevens E., and Tomlinson D. R. (1995) Targeted delivery of nerve growth factor via fibronectin conduits assists nerve regeneration in control and diabetic rats. Eur. J. Neurosci. 7, 2220–2225.PubMedGoogle Scholar
  90. 90.
    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.PubMedGoogle Scholar
  91. 91.
    Funakoshi H., Frisen J., Barbany G., Timmusk T., Zachrisson O., Verge V. M., 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.PubMedGoogle Scholar
  92. 92.
    Griesbeck O., Parsadanian A. S., Sendtner M., and Thoenen H. (1995) Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function. J. Neurosci. Res. 42, 21–33.PubMedGoogle Scholar
  93. 93.
    Acheson A., Conover J. C., Fandl J. P., De Chiara T. M., Russel M., Thadani A., et al. (1995) A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374, 450–453.PubMedGoogle Scholar
  94. 94.
    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.PubMedGoogle Scholar
  95. 95.
    Johnson E. M., Taniuchi M., and DeStefano P. S. (1988) Expression and possible function of nerve growth factor receptors on Schwann cells. Trends Neurosci. 11, 299–304.PubMedGoogle Scholar
  96. 96.
    Anton E. S., Weskamp G., Reichardt L. F., and Matthew W. D. (1994) Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc. Natl. Acad. Sci. USA 91, 2795–2799.PubMedGoogle Scholar
  97. 97.
    Meier C., Parmantier E., Brennan A., Mirsky R., and Jessen T. R. (1999) Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB. J. Neurosci. 19, 3847–3859.PubMedGoogle Scholar
  98. 98.
    Verge V. M., and Richardson P. M., Wiesenfeld-Hallin Z., and Hökfelt T. (1995) Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J. Neurosci. 15, 2081–2096.PubMedGoogle Scholar
  99. 99.
    Ohara S., Tantuwaya V., Distefano P. S., and Schmidt R. E. (1995) Exogenous NT-3 mitigates the transganglionic neuropeptide Y response to sciatic nerve injury. Brain Res. 699, 143–148.PubMedGoogle Scholar
  100. 100.
    Sato A., Sato Y., and Suzuki H. (1985) Aging effects on conduction velocities of myelinated and unmyelinated fibers of peripheral nerves. Neurosci. Lett. 53, 15–20.PubMedGoogle Scholar
  101. 101.
    Norris A. H., Shock N. W., and Wagman I. H. (1953) Age changes in the maximum conduction velocity of motor fibers of human ulnar nerves. J. Appl. Physiol. 5, 589–593.PubMedGoogle Scholar
  102. 102.
    Munson J. B., Johnson R. D., and Mendell L. M. (1997) NT-3 increases amplitude of EPSPs produced by axotomized group Ia afferents. J. Neurophysiol. 77, 2209–12.PubMedGoogle Scholar
  103. 103.
    Munson J. B. and McMahon S. B. (1997) Effects of GDNF on axotomised sensory and motor neurons in adult rats. Eur. J. Neurosci. 9, 1126–1129.PubMedGoogle Scholar
  104. 104.
    Konings P. N., Makkink W. K., Van Deft A. M., and Ruigt G. S. (1994) Reversal by NGF of cytostatic drug-induced reduction of neurite outgrowth in rat dorsal root ganglia in vitro. Brain Res. 640, 195–204.PubMedGoogle Scholar
  105. 105.
    Gao W. Q., Dybdal N., Shinsky N., and Murnane A. (1995) Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy. Ann. Neurol. 38, 30–37.PubMedGoogle Scholar
  106. 106.
    Helgren M. E., Cliffer K. D., Torrento K., Cavnor C., Curtis R., DiStefano P. S., et al. (1997) Neurotrophin-3 administration attenuates deficits of pyridoxine-induced large-fiber sensory neuropathy. J Neuroscience 17, 372–382.Google Scholar
  107. 107.
    McMahon S. B. and Priestley J. V. (1995) Peripheral neuropathies and neurotrophic factors: animal models and clinical perspectives. Curr. Opin. Neurobiol. 5, 616–24.PubMedGoogle Scholar
  108. 108.
    Bradbury E. J., Khemani S., King V. R., Priestley J. V., and McMahon S. B. (1999) NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord. Eur. J. Neurosci. 11, 3873–3883.PubMedGoogle Scholar
  109. 109.
    Gold B. G., Mobley W. C., and Matheson S. F. (1991) Regulation of axonal caliber, neurofilament content, and nuclear localization in mature sensory neurons by nerve growth factor. J. Neurosci. 11, 943–955.PubMedGoogle Scholar
  110. 110.
    Lindenbaum M. H., Carbonetto S., Grosveld F., Flavell D., and Mushynski W. E. (1988) Transcriptional and post-transcriptional effects of nerve growth factor on expression of the three neurofilament subunits in PC-12 cells. J. Biol. Chem. 263, 5662–5667.PubMedGoogle Scholar
  111. 111.
    Verge V. M., Tetzlaff W., Bisby M. A., and Richardson P. M. (1990) Influence of nerve growth factor on neurofilament gene expression in mature primary sensory neurons. J. Neurosci. 10, 2018–2025.PubMedGoogle Scholar
  112. 112.
    Novikov L. V., Novikova L. N., and Kellerth J. O. (1999) BDNF preserves MAP2 expression and dendritic architecture in axotomized adult spinal motoneurons. Thesis, Umeå University, Umeå, Sweden.Google Scholar
  113. 113.
    Chao M. V. and Hempstead B. L. (1995) p75 and Trk: a two-receptor system. Trends Neurosci. 18, 321–326.PubMedGoogle Scholar
  114. 114.
    Peterson D. A., Dickinson-Anson H. A., Leppert J. T., Lee K. F., and Gage F. H. (1999) Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J. Comp. Neurol. 404, 1–20.PubMedGoogle Scholar
  115. 115.
    Barker P. A. and Shooter E. M. (1994) Disruption of NGF binding to the low affinity neurotrophin receptor p75LNTR reduces NGF binding to TrkA on PC12 cells. Neuron 13, 203–215.PubMedGoogle Scholar
  116. 116.
    Hempstead B. L., Martin-Zanca D., Kaplan D. R., Parada L. F., and Chao M. V. (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350, 678–683.PubMedGoogle Scholar
  117. 117.
    Miller F. D., Speelman A., Mathew T. C., Fabian J., Chang E., Pozniak C., and Toma J. G. (1994) Nerve growth factor derived from terminals selectively increases the ratio of p75 to trkA NGF receptors on mature sympathetic neurons. Dev. Biol. 161, 206–217.PubMedGoogle Scholar
  118. 118.
    Ibanez C. F., Ebendal T., Barbany G., Murray-Rust J., Blundell T. L., and Persson H. (1992) Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product. Cell 69, 329–341.PubMedGoogle Scholar
  119. 119.
    Lee K. F., Bachman K., Landis S., and Jaenisch R. (1994) Dependence on p75 for innervation of some sympathetic targets. Science 263, 1447–1449.PubMedGoogle Scholar
  120. 120.
    Rydén M., Murray-Rust J., Glass D., Ilag L. L., Trupp M., Yancopoulos G. D., et al. (1995) Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling. EMBO J. 14, 1979–1990.PubMedGoogle Scholar
  121. 121.
    Lee K. F., Li E., Huber L. J., Landis S. C., Sharpe A. H., Chao M. V., and Jaenisch R. (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737.749.PubMedGoogle Scholar
  122. 122.
    Wiese S., Metzger F., Holtmann B., and Sendtner M. (1999) The role of p75NTR in modulating neurotrophin survival effects in developing motoneurons. Eur. J. Neurosci. 11, 1668–1676.PubMedGoogle Scholar
  123. 123.
    Rabizadeh S., Oh J., Zhong L. T., Yang J., Bitler C. M., Butcher L. L., and Bredesen D. E. (1993) Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348.PubMedGoogle Scholar
  124. 124.
    Verdi J. M., Birren S. J., Ibanez C. F., Persson H., and Kaplan D. R. (1994) p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells. Neuron 12, 733–745.PubMedGoogle Scholar
  125. 125.
    Carter B. D., Kaltschmidt C., Kaltschmidt B., Offenhauser N., Bohm-Matthaei R., Baeuerle P. A., and Barde Y. A. (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272, 542–5.PubMedGoogle Scholar
  126. 126.
    Casaccia-Bonnefil P., Carter B. D., Dobrowsky R. T., and Chao M. V. (1996) Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719.PubMedGoogle Scholar
  127. 127.
    Frade J. M., Rodriguez-Tebar A., and Barde Y. A. (1996) Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 383, 166–8.PubMedGoogle Scholar
  128. 128.
    Carter B. D. and Lewin G. R. (1997) Neurotrophins live or let die: does p75NTR decide? Neuron 18, 187–190.PubMedGoogle Scholar
  129. 129.
    Dechant G. and Barde Y. A. (1997) Signalling through the neurotrophin receptor p75NTR. Curr. Opin. Neurobiol. 7, 413–418.PubMedGoogle Scholar
  130. 130.
    Bredesen D. E. and Rabizadeh S. (1997) p75NTR and apoptosis: Trk-dependent and Trk-independent effects. Trends Neurosci. 20, 287–290.PubMedGoogle Scholar
  131. 131.
    Bothwell M. (1995) Functional interactions of neurotrophins and neurotrophin receptors. Ann. Rev. Neurosci. 18, 223–253.PubMedGoogle Scholar
  132. 132.
    Curtis R., Adryan K. M., Stark J. L., Park J. S., Compton D. L., Weskamp G., et al. (1995) Differential role of the low affinity neurotrophin receptor (p75) in retrograde axonal transport of the neurotrophins. Neuron 14, 1201–11.PubMedGoogle Scholar
  133. 133.
    Delcroix J. D., Tomlinson D. R., and Fernyhough P. (1997) Diabetes and axotomy-induced deficits in retrograde axonal transport of nerve growth factor correlate with decreased levels of p75LNTR protein in lumbar dorsal root ganglia. Mol. Brain Res. 51, 82–90.PubMedGoogle Scholar
  134. 134.
    Davies A. M., Lee K. F., and Jaenisch R. (1993) p75-deficient trigeminal sensory neurons have an altered response to Ngf but not to other neurotrophins. Neuron 11, 565–574.PubMedGoogle Scholar
  135. 135.
    Bennett D. L., Michael G. J., Ramachandran N., Munson J. B., Averill S., Yan Q., et al. (1998) A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J. Neurosci. 18, 3059–3072.PubMedGoogle Scholar
  136. 136.
    Molliver D. C., Wright D. E., Leitner M. L., Parsadanian A. S., Doster K., Wen D., et al. (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19, 849–861.PubMedGoogle Scholar
  137. 137.
    Naveilhan P., ElShamy W. M., and Ernfors P. (1997) Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFRalpha after sciatic nerve lesion in the mouse. Eur. J. Neurosci. 9, 1450–1460.PubMedGoogle Scholar
  138. 138.
    Trupp M., Belluardo N., Funakoshi H., and Ibanez C. F. (1997) Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J. Neurosci. 17, 3554–3567.PubMedGoogle Scholar
  139. 139.
    Davis B., Fundin B., Albers K., Goodness T., Cronk K., and Rice F. (1997) Overexpression of nerve growth factor in skin causes preferential increases among innervation to specific sensory targets. J. Comp. Neurol. 387, 489–506.PubMedGoogle Scholar
  140. 140.
    Fundin B. T., Silos-Santiago I., Ernfors P., Fagan A. M., Aldskogius H., DeChiara T. M., et al. (1997) Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR. Dev. Biol. (Orlando) 190, 94–116.Google Scholar
  141. 141.
    Rice F., Albers K., Davis B., Silos-Santiago I., Wilkinson G., LeMaster A., et al. (1998) Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR. Dev. Biol. 198, 57–81.PubMedGoogle Scholar
  142. 142.
    Airaksinen M. S., Koltzenburg M., Lewin G. R., Masu Y., Helbig C., Wolf E., et al. (1996) Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. Neuron 16, 287–95.PubMedGoogle Scholar
  143. 143.
    Isaacson L. G. and Crutcher K. A. (1998) Uninjured aged sympathetic neurons sprout in response to exogenous NGF in vivo. Neurobiol. Aging 19, 333–339.PubMedGoogle Scholar
  144. 144.
    Santer R. M. (1993) Quantitative analysis of the cervical sympathetic trunk in young adult and aged rats. Mech. Ageing Dev. 67, 289–98.PubMedGoogle Scholar
  145. 145.
    Gavazzi I. and Cowen T. (1993) Axonal regeneration from transplanted sympathetic ganglia is not impaired by age. Exp. Neurol. 122, 57–64.PubMedGoogle Scholar
  146. 146.
    Thomas P. K. and Tomlinson D. R. (1992) Diabetic and hypoglycaemic neuropathy., in Peripheral Neuropathy (Dyck P. J., Thomas P. K., Griffin J. W., Low P. A., and Poduslo J. F. eds.), W.B. Saunders, Philadelphia, pp. 1219–1250.Google Scholar
  147. 147.
    Anand P. (1996) Neurotrophins and peripheral neuropathy. Phil. Trans. Royal Soc. London — Series B: Biol. Sci. 351, 449–54.Google Scholar
  148. 148.
    Fernyhough P., Diemel L. T., Brewster W. J., and Tomlinson D. R. (1995) Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J. Neurochem. 64, 1231–7.PubMedCrossRefGoogle Scholar
  149. 149.
    Van Steenis G. and Kroes R. (1971) Changes in the nervous system and musculature of old rats. Vet. Pathol. 8, 320–332.PubMedGoogle Scholar
  150. 150.
    Burek J. D., van der Kogel A. J., and Hollander C. F. (1976) Degenerative myelopathy in three strains of aging rats. Vet. Pathol. 13, 321–331.PubMedGoogle Scholar
  151. 151.
    Sharma A. K., Bajada S. and Thomas P. K. (1980) Age changes in the tibial and plantar nerves of the rat. J. Anat. 130, 417–428.PubMedGoogle Scholar
  152. 152.
    Krinke G. (1983) Spinal radiculoneuropathy in aging rats: demyelination secondary to neuronal dwindling? Acta Neuropathol. (Berl.) 59, 63–69.Google Scholar
  153. 153.
    Edström L. and Larsson L. (1987) Effects of age on muscle fibre characteristics of fast- and slow-twitch single motor units in the rat. J. Physiol. 392, 129–145.PubMedGoogle Scholar
  154. 154.
    Son Y. J., Trachtenberg J. T., and Thompson W. J. (1996) Schwann cells induce and guide sprouting and reinnervation of neuromuscular junctions. Trends Neurosci. 19, 280–285.PubMedGoogle Scholar
  155. 155.
    Kawabuchi M., Zhou C., Nakamura K. and Hirata K. (1995) Morphological features of collateral innervation and supernumerary innervation in the skeletal muscles of presenile rats. Anatomischer Anzeiger 177, 251–65.PubMedGoogle Scholar
  156. 156.
    Kanda K. and Hashizume K. (1991) Recovery of motor-unit function after peripheral nerve injury in aged rats. Neurobiol. Aging 12, 271–276.PubMedGoogle Scholar
  157. 157.
    Campion D. R. (1984) The muscle satellite cell: a review. Int. Rev. Cytol. 87, 225–51.PubMedGoogle Scholar
  158. 158.
    Schultz E. and Lipton B. H. (1982) Skeletal muscle satellite cells: changes in proliferation potential as a function of age. Mech. Ageing Dev. 20, 377–83.PubMedGoogle Scholar
  159. 159.
    Emery A. (1993) Duchenne muscular dystrophy, Oxford Univ Press, New York.Google Scholar
  160. 160.
    Ferrari G., Cusella-de Angelis G., Coletta M., Paolucci E., Stornauolo A., Cossu G. and Mavilio F. (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530.PubMedGoogle Scholar
  161. 161.
    Ernfors P., Wetmore C., Olson L. and Persson H. (1990) Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 5, 511–526.PubMedGoogle Scholar
  162. 162.
    Funakoshi H., Belluardo N., Arenas E., Yamamoto Y., Casabona A., Persson H. and Ibanez C. F. (1995) Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science 268, 1495–1499.PubMedGoogle Scholar
  163. 163.
    Ip N. Y., Ibánez C. F., Nye S. H., McClain J., Jones P. F., Gies D. R., Belluscio L., Le Beau M. M., Espinosa III R., Squinto S. P., Persson H. and Yancopoulos G. D. (1992) Mammalian neurotrophin-4: Structure, chromosomal localization, tissue distribution, and receptor specificity. Proc. Natl. Acad. Sci. USA 89, 3060–3064.PubMedGoogle Scholar
  164. 164.
    Timmusk T., Belluardo N., Metsis M., and Persson H. (1993) Widespread and developmentally regulated expression of neurotrophin-4 mRNA in rat brain and peripheral tissues. Eur. J. Neurosci. 5, 605–13.PubMedGoogle Scholar
  165. 165.
    Alcántara S., Frisén J., del Rio J. A., Soriano E., Barbacid M. and Silos-Santiago I. (1997) TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy induced cell death. J. Neurosci. 17, 3623–3633.PubMedGoogle Scholar
  166. 166.
    Piehl F., Frisen J., Risling M., Hökfelt T. and Cullheim S. (1994) Increased trkB mRNA expression by axotomized motoneurones. Neuroreport 5, 697–700.PubMedGoogle Scholar
  167. 167.
    Johnson H., Hökfelt T. and Ulfhake B. (1996) Decreased expression of TrkB and TrkC mRNAs in spinal motoneurons of aged rats. Eur. J. Neurosci. 8, 494–499.PubMedGoogle Scholar
  168. 168.
    Yan Q., Snider W. D., Pinzone J. J., and Johnson E. M., Jr. (1988) Retrograde transport of nerve growth factor (NGF) in motoneurons of developing rats: assessment of potential neurotrophic effects. Neuron 1, 335–43.PubMedGoogle Scholar
  169. 169.
    Helke C. J., Adryan K. M., Fedorowicz J., Zhuo H., Park J. S., Curtis R., Radley H. E., and Distefano P. S. (1998) Axonal transport of neurotrophins by visceral afferent and efferent neurons of the vagus nerve of the rat. J. Comp. Neurol. 393, 102–17.PubMedGoogle Scholar
  170. 170.
    DiStefano P. S., Friedman B., Radziejewesk C., Alexander C., Boland P., Schieck C., Lindsay R. M., and Wiegand S. J. (1992) The neurotrophins BDNF, NT 3 and NGF display distinct patterns of retrograde axonal transport in peripheral and central axons. Neuron 8, 983–993.PubMedGoogle Scholar
  171. 171.
    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.PubMedGoogle Scholar
  172. 172.
    Munson J. B., Shelton D. L., and McMahon S. B. (1997) Adult mammalian sensory and motor neurons: roles of endogenous neurotrophins and rescue by exogenous neurotrophins after axotomy. Journal of Neuroscience 17, 470–6.PubMedGoogle Scholar
  173. 173.
    Wong, V., Arriaga R., Ip N. Y., and Lindsay R. M. (1993) The neurotrophins BDNF, NT-3 and NT-4/5, but not NGF, up-regulate the cholinergic phenotype of developing motor neurons. Eur. J. Neurosci. 5, 466–74.PubMedGoogle Scholar
  174. 174.
    Novikov L., Novikova L. and Kellerth J. O. (1995) Brain-derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult rat spinal motoneurons after ventral root avulsion. Neurosci. Lett. 200, 45–8.PubMedGoogle Scholar
  175. 175.
    Novikov L., Novikova L. and Kellerth J. O. (1997) Brain-derived neurotrophic factor promotes axonal regenration and long-term survival of adult rat spinal motoneurons in vivo. Neuroscience 79, 765–74.PubMedGoogle Scholar
  176. 176.
    Friedman B., Kleinfeld D., Ip N. Y., Verge V. M. K., Moulton R., Boland P., Zlochenko E., Lindsay R. M., and Liu L. (1995) BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons. J. Neurosci. 15, 1044–1056.PubMedGoogle Scholar
  177. 177.
    Vejsada R., Tseng J. L., Lindsay R. M., Acheson A., Aebischer P. and Kato A. C. (1998) Synergistic but transient rescue effects of BDNF and GDNF on axotomized neonatal motoneurons. Neuroscience 84, 129–139.PubMedGoogle Scholar
  178. 178.
    Simon M., Terenghi G., Green C. J., and Coulton G. R. (2000) Differential effects of NT-3 on reinnervation of the fast extensor digitorum longus (EDL) and the slow soleus muscle of the rat. Eur. J. Neurosci 12, 863–871.PubMedGoogle Scholar
  179. 179.
    Munson J. B., Foehring R. C., Mendell L. M., and Gordon T. (1997) Fast-to-slow conversion following chronic low-frequency activation of medical gastrocnemius muscle in cats. II. Motoneuron properties. J. Neurophysiol. 77, 2605–15.PubMedGoogle Scholar
  180. 180.
    Xie K., Wang T., Olafsson P., Mizuno K. and Lu B. (1997) Activity-dependent expression of NT-3 in muscle cells in culture: implications in the development of neuromuscular junctions. J. Neurosci. 17, 2947–58.PubMedGoogle Scholar
  181. 181.
    Wang T., Xie K. and Lu B. (1995) Neurotrophins promote maturation of developing neuromuscular synapses. J. Neurosci. 15, 4796–805.PubMedGoogle Scholar
  182. 182.
    Wang X. H., Berninger B. and Poo M. (1998) Localized synaptic actions of neurotrophin-4. J. Neurosci. 18, 4985–4992.PubMedGoogle Scholar
  183. 183.
    Koliatsos V. E., Cayouette M. H., Berkemeier L. R., Clatterbuck R. E., Price D. L., and Rosenthal A. (1994) Neurotrophin 4/5 is a trophic factor for mammalian facial motor neurons. Proc. Natl. Acad. Sci. USA 91, 3304–8.PubMedGoogle Scholar
  184. 184.
    Ernfors P., Henschen A., Olson L. and Persson H. (1989) Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2, 1605–13.PubMedGoogle Scholar
  185. 185.
    Koliatsos V. E., Crawford T. O., and Price D. L. (1991) Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons. Brain Res. 549, 297–304.PubMedGoogle Scholar
  186. 186.
    Johnson H., Hökfelt T. and Ulfhake B. (1999) Expression of p75NTR, trkB and trkC in nonmanipulated and axotomized motoneurons of aged rats. Mol. Brain Res. 69, 21–34.PubMedGoogle Scholar
  187. 187.
    Hammarberg H., Piehl F., Risling M. and Cullheim S. (2000) Differential regulation of trophic factor and receptor mRNAs after peripheral and central axotomy of rat spinal motoneurons. Thesis, Karolinska Institutet, Stockholm, SwedenGoogle Scholar
  188. 188.
    Kobayashi N. R., Bedard A. M., Hincke M. T., and Tetzlaff W. (1996) Increased expression of BDNF and trkB mRNA in rat facial motoneurons after axotomy. Eur. J. Neurosci. 8, 1018–29.PubMedGoogle Scholar
  189. 189.
    Chase M. H., Morales F. R., Boxer P. A., and Fung S. J. (1985) Aging of motoneurons and synaptic processes in the cat. Exp. Neurol. 90, 471–478.PubMedGoogle Scholar
  190. 190.
    Falls D. L., Rosen K. M., Corfas G., Lane W. and Fischbach G. D. (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis is a member of the neu ligand family. Cell 72, 801–815.PubMedGoogle Scholar
  191. 191.
    Lemke G. (1996) Neuregulins in development. Mol. Cell. Neurosci. 7, 247–262.PubMedGoogle Scholar
  192. 192.
    Carraway III K. L. and Cantley L. C. (1994) A neur acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell 78, 5–8.PubMedGoogle Scholar
  193. 193.
    Loeb J. A. and Fischbach G. D. (1997) Neurotrophic factors increase neuregulin expression in embryonic ventral spinal cord neurons. J. Neurosci. 17, 1416–1424.PubMedGoogle Scholar
  194. 194.
    Greeson D. M., Moix L., Meier M., Armstrong D. M., and Wiley R. G. (1992) A continuing signal maintains NGF receptor expression in hypoglossal motor neurons after crush injury. Brain Res. 594, 351–355.PubMedGoogle Scholar
  195. 195.
    Irie F. and Hirabayashi Y. (1999) Ceramide prevents motoneuronal cell death through inhibition of oxidative signal. Neurosci. Res. 35, 135–144.PubMedGoogle Scholar
  196. 196.
    Nguyen Q. T., Parsadanian A. S., Snider W. D., and Lichtman J. W. (1998) Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science 279, 1725–1729.PubMedGoogle Scholar
  197. 197.
    Sagot Y., Tan S. A., Hammang J. P., Aebischer P. and Kato A. C. (1996) GDNF slows loss of motoneurons but not axonal degeneration or premature death of pmn/pmn mice. J. Neurosci. 16, 2335–41.PubMedGoogle Scholar
  198. 198.
    Suzuki H., Hase A., Miyata Y., Arahata K. and Akazawa C. (1999) Prominent expression of glial cell line-derived neurotrophic factor in human skeletal muscle. J. Comp. Neurol. 402, 303–312.Google Scholar
  199. 199.
    Levi-Montalcini R. (1987) The nerve growth factor 35 years later. Science 237, 1154–1162.PubMedGoogle Scholar
  200. 200.
    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, 149–152.PubMedGoogle Scholar
  201. 201.
    Ernfors P., Ibáne C., Ebendal T., Olson L. and Persson H. (1990) 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. USA 87, 5454–5458.PubMedGoogle Scholar
  202. 202.
    Hohn A., Leibrock J., Bailey K. and Barde Y. A. (1990) Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature 344, 339–341.PubMedGoogle Scholar
  203. 203.
    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.PubMedGoogle Scholar
  204. 204.
    Rosenthal A., Goeddel D. V., Nguyen T., Lewis M., Shih A., Laramee G. R., Nikolics K. and Winslow J. W. (1990) Primary structure and biological activity of a novel human neurotrophic factor. Neuron 4, 767–773.PubMedGoogle Scholar
  205. 205.
    Berkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., and Rosenthal A. (1991) Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron 7, 857–866.PubMedGoogle Scholar
  206. 206.
    Hallböök F., Ibanez C. F., and Persson H. (1991) Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron 6, 845–858.PubMedGoogle Scholar
  207. 207.
    Barbacid M. (1994) The Trk family of neurotrophin receptors. J Neurobiol 25, 1386–403.PubMedGoogle Scholar
  208. 208.
    Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., and Shooter E. M. (1987) Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 325, 593–596.PubMedGoogle Scholar
  209. 209.
    Rodriguez-Tébar A., Dechant G. and Barde Y. A. (1990) Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron 4, 487–492.PubMedGoogle Scholar
  210. 210.
    Rodriguez-Tébar 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. 11, 917–922.PubMedGoogle Scholar
  211. 211.
    Kaplan D. R., Hempstead B. L., Martin-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, 554–558.PubMedGoogle Scholar
  212. 212.
    Klein R., Jing S., Nandurin V., O’Rourke E. and Barbacid M. (1991) The trk protooncogene encodes a receptor for nerve growth factor. Cell 65, 189–197.PubMedGoogle Scholar
  213. 213.
    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., Nikolics K. and Parada L. F. (1991) The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65, 895.903.PubMedGoogle Scholar
  214. 214.
    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.PubMedGoogle Scholar
  215. 215.
    Lamballe F., Klein R. and Barbacid M. (1991) trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 66, 967–979.PubMedGoogle Scholar
  216. 216.
    Cordon-Cardo C., Tapley P., Jing S. Q., Nanduri V., O’Rourke E., Lamballe F., Kovary K., Klein R., Jones K. R., Reichardt L. F., and Barbacid M. (1991) The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3. Cell 66, 173–183.PubMedGoogle Scholar
  217. 217.
    Snider W. D. (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638.PubMedGoogle Scholar
  218. 218.
    Lewin G. R. (1996) Neurotrophins and the specification of neuronal phenotype. Philosophical Transactions of the Royal Society of London — Series B: Biological Sciences 351, 405–411.PubMedGoogle Scholar
  219. 219.
    Klein R., Conway D., Parada L. F., and Barbacid M. (1990) The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61, 647–656.PubMedGoogle Scholar
  220. 220.
    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.PubMedGoogle Scholar
  221. 221.
    Eide F. F., Vining E. R., Eide R. 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.PubMedGoogle Scholar
  222. 222.
    Biffo S., Offenhäuser N., Carter B. D., and Barde Y. A. (1995) Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development 121, 2461–2470.PubMedGoogle Scholar
  223. 223.
    Lin L. F., Doherty D. H., Lile J. D., Bektesh S. and Collins F. (1993) GDNF: a glial cell linederived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132.PubMedGoogle Scholar
  224. 224.
    Kotzbauer P. T., Lampe P. A., Heuckeroth R. O., Golden J. P., Creedon D. J., Johnson E. M., Jr. and Milbrandt J. (1996) Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384, 467–470.PubMedGoogle Scholar
  225. 225.
    Baloh R. H., Transey M. G., Lampe P. A., Fahrner T. J., Enomoto H., Simburger K. S., Leitner M. L., Araki T., Johnson Jr. E. M., and Milbrandt J. (1998) Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRa3-RET receptor complex. Neuron 21, 1291–1302.PubMedGoogle Scholar
  226. 226.
    Milbrandt J., de Sauvage F. J., Fahrner T. J., Baloh R. H., Leitner M. L., Tansey M. G., et al. (1998) Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 20, 245–253.PubMedGoogle Scholar
  227. 227.
    Henderson C. E., Phillips H. S., Pollock R. A., Davies A. M., Lemeulle C., Armanini M., et al. (1994) GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266, 1062–1064.PubMedGoogle Scholar
  228. 228.
    Buj-Bello A., Buchman V. L., Horton A., Rosenthal A., and Davies A. M. (1995) GDNF is an age-specific survival factor for sensory and autonomic neurons. Neuron 15, 821–828.PubMedGoogle Scholar
  229. 229.
    Ebendal T., Tomac A., Hoffer B. J., and Olson L. (1995) Glial cell line-derived neurotrophic factor stimulates fiber formation and survival in cultured neurons from peripheral autonomic ganglia. J. Neurosci. Res. 40, 276–284.PubMedGoogle Scholar
  230. 230.
    Li L., Wu W., Lin L. H., Lei M., Oppenheim R. W., and Houenou L. J. (1995) Rescue of adult mouse motoneurons from injuryinduced cell death by glial cell line-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 92, 9771–9775.PubMedGoogle Scholar
  231. 231.
    Oppenheim R. W., Houenou L. J., Johnson J. E., Lin L. F., Li L., Lo A. C., et al. (1995) Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature 373, 344–346.PubMedGoogle Scholar
  232. 232.
    Trupp M., Ryden M., Jornvall H., Funakoshi H., Timmusk T., Arenas E., and Ibanez C. F. (1995) Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. J. Cell Biol. 130, 137–148.PubMedGoogle Scholar
  233. 233.
    Durbec P., Marcos-Gutierrez C. V., Kilkenny C., Grigoriou M., Wartiowaara K., Suvanto P., et al. (1996) GDNF signalling through the Ret receptor tyrosine kinase [see comments]. Nature 381, 789–793.PubMedGoogle Scholar
  234. 234.
    Trupp M., Arenas E., Fainzilber M., Nilsson A. S., Sieber B. A., Grigoriou M., et al. (1996) Functional receptor for GDNF encoded by the c-ret proto-oncogene [see comments]. Nature 381, 785–788.PubMedGoogle Scholar
  235. 235.
    Jing S., Wen D., Yu Y., Holst P. L., Luo Y., Fang M., et al. (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85, 1113–1124.PubMedGoogle Scholar
  236. 236.
    Treanor J. J., Goodman L., de Sauvage F., Stone D. M., Poulsen K. T., Beck C. D., et al. (1996) Characterization of a multicomponent receptor for GDNF [see comments]. Nature 382, 80–83.PubMedGoogle Scholar
  237. 237.
    Baloh R. H., Tansey M. G., Golden J. P., Creedon D. J., Heuckeroth R. O., Keck C. L., et al. (1997) TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 18, 793–802.PubMedGoogle Scholar
  238. 238.
    Jing S., Yu Y., Fang M., Hu Z., Holst P. L., Boone T., et al. (1997) GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J. Biol. Chem. 272, 33,111–33,117.Google Scholar
  239. 239.
    Klein R. D., Sherman D., Ho W. H., Stone D., Bennett G. L., Moffat B., et al. (1997) A GPI-linked protein that interacts with RET to form a candidate neurturin receptor. Nature 387, 717–721.PubMedGoogle Scholar
  240. 240.
    Baloh R. H., Gorodinsky A., Golden J. P., Tansey M. G., Keck C. L., Popescu N. C., et al. (1998) GFRalpha3 is an orphan member of the GDNF/neurturin/persephin receptor family. Proc. Natl. Acad. Sci. USA 95, 5801–5806.PubMedGoogle Scholar
  241. 241.
    Enokido Y., de Sauvage F., Hongo J. A., Ninkina N., Rosenthal A., Buchman V. L., and Davies A. M. (1998) GFRalpha4 and the tyrosine kinase Ret form a functional receptor complex for perspephin. Curr. Biol. 8, 1019–1022.PubMedGoogle Scholar
  242. 242.
    Thompson J., Doxakis E., Pinon L. G., Strachan P., Buj-Bello A., Wyatt S., et al. (1998) GFRalpha-4, a new GDNF family receptor. Mol Cell Neurosci 11, 117–126.PubMedGoogle Scholar
  243. 243.
    Schaar D. G., Sieber B. A., Dreyfus C. F., and Black I. B. (1993) Regional and cell-specific expression of GDNF in rat brain. Exp. Neurol. 124, 368–371.PubMedGoogle Scholar
  244. 244.
    Mikaels Å., Livet J., Westphal H., de Lapeyriére O., and Ernfors P. (2000) A dynamic regulation of GDNF-family receptors correlates with a specific trophic dependency of cranial motor neuron subpopulations during development. Eur. J. Neurosci. 12, 446–456.PubMedGoogle Scholar
  245. 245.
    Wang H., Rivero-Melian C., Robertson B., and Grant G. (1994) Transganglionic transport and binding of the isolectin B4 from Griffonia simplicifolia I in rat primary sensory neurons. Neuroscience 62, 539–551.PubMedGoogle Scholar
  246. 246.
    Robertson B., Perry M. J., and Lawson S. N. (1991) Populations of rat spinal primary afferent neurons with choleragenoid binding compared with those labelled by markers for neurofilament and carbohydrate groups: a quantitative immunocytochemical study. J. Neurocytol. 20, 387–395.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • Brun Ulfhake
    • 1
  • Esbjorn Bergman
    • 1
  • Erik Edström
    • 1
  • Bengt T. Fundin
    • 1
    • 2
  • Hans Johnson
    • 1
  • Susanna Kullberg
    • 1
  • Yu Ming
    • 1
  1. 1.Department of NeuroscienceKarolinska InstitutetStockholmSweden
  2. 2.Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden

Personalised recommendations