As most elegantly confirmed by the recent success in deriving mice with null mutations in the genes for specific neurotrophic factors or their respective receptors, it is clear that neurotrophic factors alone or in combination are essential for the development of many classes of neurons. Specific neurotrophic factors have now been characterized that have actions on primary sensory afferents, sympathetic and parasym pathetic neurons, and motor neurons—the major contributors to the axon bundles that comprise the periph eral nervous system. The peripheral tissues or "end organs" that these neurons innervate have traditionally been thought of as the key source of neurotrophic factor support, but it is now evident that this "target- derived neurotrophic factor hypothesis" has restricted validity. Rather, the totality of neurotrophic support required to promote the survival, maturation, and maintenance of a neuron appears to be derived not only from targets, but also from support cells and possibly even neurons themselves. In this article, we review the role played by multiple sources of neurotrophic factors, especially factors derived from non-neuronal cells, not only in development, but also in the maintenance and regenerative responses of the adult PNS. In par ticular, we focus on neurotrophic factors of the neurotrophin family and ciliary neurotrophic factor. The Neuro scientist 1:192-199, 1995
Fawcett JW, Keynes RJPeripheral nerve regeneration. Ann Rev Neurosci1990;13:43-60.
2.
Richardson PM , McGuiness U., Aguayo AGAxons from CNS neurones regenerate into PNS grafts. Nature1980;284:264-265.
3.
Salzer JL, Williams AK, Glazer L., Bunge RPStudies of Schwann cell proliferation III: evidence for surface localization of the neurite mitogen. J Cell Biol1980;84:767-778.
4.
LeBeau JM, LaCorbiere M., Powell HC, Ellisman MH, Schubert D.Extracellular fluid conditioned during peripheral nerve regeneration stimulates Schwann cell adhesion, migration and proliferation. Brain Res1988;459:93-104.
5.
Siironen J., Collan Y., Roytta M.Axonal reinnervation does not influence Schwann cell proliferation after rat sciatic nerve transection. Brain Res1994;654:303-311.
6.
Sobue G., Brown MJ, Kim S., Pleasure D.Axolemma is a mitogen for the human Schwann cell. Ann Neurol1984;15:449-452.
7.
Yoshino JE, Dinneen MP, Lewis BL, Meador Woodruff JH, DeVries GHDifferential proliferative responses of cultured Schwann cells to axolemma and myelin-enriched fractions I. Biochemical studies. J Cell Biol1984;99:2309-2313.
8.
Tsao JW, Brown MC, Carden MJ, McLean WG, Perry VHLoss of the compound action potential: an electrophysiological, biochemical and morphological study of early events in axonal degeneration in the C57BL/OLA mouse. Eur J Neurosci1994;6:516-524.
9.
Anton ES, Sandrock AW Jr, Matthew WDMerosin promotes neunte growth and Schwann cell migration in vitro and nerve regeneration in vivo: evidence using an antibody to Merosm, ARM-1 . Dev Biol1994;164:133-146.
10.
Hall SM, Gregson NAThe effects of mitomyocm C on the process of regeneration in the mammalian peripheral nervous system. Neuropathol Appl Neurobiol1977;3:65-78.
11.
Liu HM, Balcovic ES, Sheff MF, Zacks SIProduction in vitro of a neurotrophic substance from proliferative neurolemma-like cells. Exp Neurol1979;64:271-283.
12.
Longo FM, Hayman GE, Ruoslahti E., Engvall E., Manthorpe M., Varon S.Neurite-promotmg factors and extracellular matrix components accumulating in vivo within nerve regeneration chambers. Brain Res1984;309:105-117.
13.
Manthorpe M. , Engvall E., Ruoslahti E., Longo FM, Davis GE, Varon S.Laminin promotes neuritic regeneration from cultured peripheral and central neurons. J Cell Biol1983;97:1882-1890.
14.
Burnham P., Raiborn C., Varon S.Replacement of nerve-growth factor by gangliomc non-neuronal cells for the survival in vitro of dissociated ganghomc neurons. Proc Natl Acad Sci U S A1972;69:3556-3560.
15.
Koliatsos VE , Price WL, Pardo CA, Price DLVentral root avulsion : an experimental model of death of adult motor neurons. J Comp Neurol1994;342:35-44.
16.
Patterson PH , Chun LYThe influence of non-neuronal cells on catecholamine and acetylcholine synthesis and accumulation in cultures of dissociated sympathetic neurons. Proc Natl Acad Sci U S A1974;71:3607-3610.
Barde Y-A.Trophic factors and neuronal survival. Neuron1989;2:1525-1534.
19.
Lmdsay RM, Wiegand SJ, Altar CA, DiStefano PS. Neurotrophic factors: from molecule to man. Trends Neurosci1994;17:182-190.
20.
Raivich G., Kreutzberg GWPathophysiology of glial growth factor receptors. Glia1994;11:129-146.
21.
Levi-Montalcini R.The nerve growth factor: thirty-five years later. EMBO J1987;6:1145-1154.
22.
Glass DJ, Yancopoulos GDThe neurotrophms and their receptors. Trends Cell Biol1993;3:262-267.
23.
Smder WDFunctions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell1994 ;77:627-638.
24.
Thoenen H., Bandtlow C., Heumann R.The physiological function of nerve growth factor in the central nervous system: comparison with the periphery. Rev Physiol Biochem Pharmacol1987;109: 145-178.
25.
Maisonpierre PC, Belluscio L., Fnedman B., et al. NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression . Neuron1990;5:501-509.
26.
Ernfors P., Merlio J-P., Persson H.Cells expressing mRNA for neurotrophms and their receptors during embryonic rat development. Eur J Neurosci1992;4:1140-1158.
27.
Funakoshi H. , Frisén J., Barbany G., et al. Differential expression of mRNAs for neurotrophms and their receptors after axotomy of the sciatic nerve. J Cell Biol1993;123:455-465.
28.
Hory-Lee F. , Russell M., Lmdsay RM, Frank E.Neurotrophm 3 supports the survival of developing muscle sensory neurons in culture. Proc Natl Acad Sci U S A1993;90:2613-2617.
29.
Helgren ME, Torrento K., DiStefano PS, Curtis R., Lmdsay RM, Wiegand SJNT-3 attenuates propnoceptive deficits in the adult rat with a large fiber neuropathy. Soc Neurosci Abstr1994;20:1106.
30.
Wong V., Amaga R., Ip NY, Lmdsay RMThe neurotrophins BDNF, NT-3 and NT-4/5, but not NGF, up-regulate the cholinergic phenotype of developing motor neurons. Eur J Neurosci1993;5:466-474.
31.
Sendtner M. , Holtmann B., Kolbeck R., Thoenen H., Barde Y-A. Brain-denved neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature1992;360:757-759.
32.
Ip NY, Yancopoulos GDReceptors and signaling pathways of ciliary neurotrophic factor and the neurotrophins . Seminars in The Neurosciences1993;5:249-257.
33.
Masu Y., Wolf E., Holtmann B., Sendtner M., Brem G., Thoenen H.Disruption of the CNTF gene results in motor neuron degeneration. Nature1993;365:27-32.
34.
Stöckli KA, Lottspeich F., Sendtner M., et al. Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. Nature1989;342:920-923.
35.
Fnedman B., Scherer SS, Rudge JS, et al. Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo. Neuron1992;9:295-305.
36.
Rende M., Muir D., Ruoslahti E., Hagg T., Varon S., Manthorpe M.Immunolocalization of ciliary neuronotrophic factor in adult rat sciatic nerve . Glia1992;5:25-32.
37.
Yamamori T. , Fukada K., Aebersold R., Korschmg S., Fann M., Patterson P.The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science1989;246:1412-1416.
38.
Barde Y-A., Lindsay RM, Monard D., Thoenen H.New factor released by cultured ghoma cells supporting survival and growth of sensory neurones. Nature1978;274:818.
39.
Lm L., Doherty D., Lile J., Bektesh S., Collins F.GDNF: A glial cell line-derived neurotrophic factor for midbrain dopammergic neurons. Science1993;260:1130-1132.
40.
Saadat S., Rohrer H., Sendtner M.Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture. J Cell Biol1989;108:1807-1816.
41.
McMahon SB, Armanini MP, Ling LH, Phillips HSExpression and coexpression of trk receptors m subpopulations of adult pnmary sensory neurons projecting to identified peripheral targets. Neuron1994;12:1161-1171.
42.
Schecterson LC, Bothwell M.Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons. Neuron1992;9:449-463.
43.
Sebert ME, Shooter EMExpression of mRNA for neurotrophic factors and their receptors in the rat dorsal root ganglion and sciatic nerve following nerve injury. J Neurosci Res1993;36:357-367.
44.
Acheson A., Conover JC, Fandl JP, DeChiara TM, Russell M., Thadani A., Squinto SP, Yancopoulos GD, Lmdsay RMA BDNF autocnne loop in adult sensory neurons prevents cell death . Nature1995;374:450-453.
45.
Meyer M., Matsuoka I., Wetmore C., Olson L., Thoenen H.Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechamsms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol1992;119:45-54.
46.
Sendtner M. , Stockli KA, Thoenen H.Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration . J Cell Biol1992; 118.139-148.
47.
Eckenstem FP , Esch F., Holbert T., Blacher RW, Nishi R.Purification and characterization of a trophic factor for embryonic peripheral neurons: comparison with fibroblast growth factors. Neuron1990 ;4:623-631.
48.
Unsicker K. , Reichert-Preibsch H., Schmidt R., Pettmann B., Labourdette G., Sensenbrenner M.Astroglial and fibroblast growth factors have neurotrophic functions for cultured peripheral and central nervous system neurons. Proc Natl Acad Sci U S A1987;84:5459-5463.
49.
Knkorian D. , Manthorpe M., Varon S.Punfied mouse Schwann cells: mitogemc effects of fetal calf serum and fibroblast growth factor. Dev Neurosci1982;5:77-91.
50.
Neuberger TJ , DeVnes GH. Distribution of fibroblast growth factor in cultured dorsal root ganglion neurons and Schwann cells. II. Redistribution after injury. J Neurocytol1993 ;22:449-460.
51.
Eccleston PA , Funa K., Heldm C-H. Expression of platelet-denved growth factor (PDGF) and PDGF alpha and beta receptors in the penpheral nervous system: an analysis of sciatic nerve and dorsal root ganglia. Dev Biol1993;155:459-470.
52.
Heumann R., Korschmg S., Bandtlow C., Thoenen H.Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transectionJ Cell Biol1987 ;104:1623-1631.
53.
Curtis R., Scherer SS, Somogyi R., et al. Retrograde axonal transport of LIF is increased by peripheral nerve injury: correlation with increased LIF expression in distal nerve. Neuron1994;12:191-204.
54.
Lindholm D. , Heumann R., Meyer M., Thoenen H.Interleukin-1 regulates synthesis of nerve growth factor in nonneuronal cells of rat sciatic nerve. Nature1987;330:658-659.
55.
Brown MC, Perry VH, Lunn RE, Gordon S., Heumann R.Macrophage dependence of penpheral sensory nerve regeneration: possible involvement of nerve growth factor. Neuron1991;6: 359-370.
56.
Hughes RA, Sendtner M., Goldfarb M., Lindholm D., Thoenen H.Evidence that fibroblast growth factor 5 is a major muscle-denved survival factor for cultured spinal motoneurons. Neuron1993;10:369-377.
57.
Helgren ME, Squinto SP, Davis HL, et al. Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle. Cell1994;76:493-504.
58.
Palmatier MA , Hartman BJ, Johnson EMDemonstration of retrogradely transported endogenous nerve growth factor in axons of sympathetic neurons . J Neurosci1984;4:751-756.
59.
Kuffler DPGrowth cones are directed up concentration gradients by factors released from denervated peripheral nerve tubes. Soc Neurosci Abstr1994;20:663.
60.
Fitzgerald M., Wall PD, Goedert M., Emson PCNerve growth factor counteracts the neurophysiological and neurochemical effects of chronic sciatic nerve transectionBrain Res1985;332: 131-141
61.
Rich KM, Pryor JC, Alexander TD, Hollowell JPNerve growth factor enhances regeneration through silicone chambers . Exp Neurol1989;105:162-170.
62.
Fnedman B., Kleinfeld D., Ip NY, et al. BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons. J Neurosci1995;15:1044-1056.
63.
Mitsumoto H. , Ikeda K., Klinkosz B., Cedarbaum JM, Wong V., Lindsay RMArrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science1994;265:1107-1110.
64.
Sendtner M. , Schmalbruch H., Stockh KA, Carroll P., Kreutzberg GW, Thoenen H.Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathyNature1992;358:502-504.
