Neurochemical Research

, Volume 21, Issue 7, pp 787–793 | Cite as

Neurotrophin-4: The odd one out in the neurotrophin family

  • Carlos F. Ibáñez
Original Articles


Neurotrophin-4 (NT-4) is a member of a family of neurotrophic factors, the neurotrophins, that control survival and differentiation of vertebrate neurons (2–4). Besides being the most recently discovered neurotrophin in mammals, and the least well understood, several aspects distinguish NT-4 from other members of the neurotrophin family. It is the most divergent member and, in contrast to the other neurotrophins, its expression is ubiquitous and appears to be less influenced by environmental signals. NT-4 seems to have the unique requirement of binding to the lowaffinity neurotrophin receptor (p75LNGFR) for efficient signalling and retrograde transport in neurons. Moreover, while all other neurotrophin knock-outs have proven lethal during early postnatal development, mice deficient in NT-4 have so far only shown minor cellular deficits and develop normally to adulthood. Is NT-4 a recent addition to the neurotrophic factor repertoire in search of a crucial function, or is it an evolutionary relic, a kind of wisdom tooth of the neurotrophin family?

Key Words

Development muscle nervous system nerve growth factor site-directed mutagenesis 


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  1. 1.
    Adams, M., et al., 1995. Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence. Nature. 377 Suppl.:3–174.PubMedGoogle Scholar
  2. 2.
    Barde, Y.-A. 1989. Trophic factors and survival. Neuron., 2:1525–1534.PubMedCrossRefGoogle Scholar
  3. 3.
    Thoenen, H. 1991. The changing scene of neurotrophic factors. Trends Neurosci. 14:165–170.PubMedCrossRefGoogle Scholar
  4. 4.
    Persson, H., and Ibáñez, C. 1993. Role and expression of neurotrophins and the trk family of tyrosine kinase receptors in neuronal growth and rescue after injury. Curr Op Neurol Neurosurg. 6:11–18.Google Scholar
  5. 5.
    Hallböök, F., Ibáñez, 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.PubMedCrossRefGoogle Scholar
  6. 6.
    Ip, N. Y., Ibáñez, 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. 1992. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution and receptor specificity. Proc Natl Acad Sci U S A. 89:3060–3064.PubMedCrossRefGoogle Scholar
  7. 7.
    Timmusk, T., Belluardo, N., Metsis, M., and Persson, H. 1993. Widespread and developmentally regulated expression of neurotrophin-4 messenger RNA in rat brain and peripheral tissues. Eur J Neurosci. 5:605–613.PubMedCrossRefGoogle Scholar
  8. 8.
    Funakoshi, H., Frisen, J., Barbany, G., Timmusk, T., Zachrisson, O., Verge, V. M. K., and Persson, H. 1993. Differential expression of messenger RNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 123:455–465.PubMedCrossRefGoogle Scholar
  9. 9.
    Funakoshi, H., Belluardo, N., Arenas, E., Yamamoto, Y., Casabona, A., Persson, H., and Ibáñez, C. F. 1995. Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science. 268:1495–1499.PubMedCrossRefGoogle Scholar
  10. 10.
    Rydén, M., Murray-Rust, J., Glass, D., Ilag, L. L., Trupp, M., Yancopoulos, G. D., McDonald, N. Q., and Ibáñez, C. E. 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
  11. 11.
    Curtis, R., Adryan, K. M., Stark, J. L., Park, J. S., Compton, D. L., Weskamp, G., Huber, L. J., Chao, M. V., Jaenisch, R., Lee, K. F., Lindsay, R. M., and Distefano, P. S. 1995. Differential role of the low affinity neurotrophin receptor (p75) in retrograde axonal transport of the neurotrophins. Neuron. 14:1201–1211.PubMedCrossRefGoogle Scholar
  12. 12.
    Conover, J. C., Erickson, J. T., Katz, D. M., Bianchi, L. M., Poueymirou, W. T., McClain, J., Pan, L., Helgren, M., Ip, N. Y., Boland, P., Friedman, B., Wiegand, S., Vejsada, R., Kato, A. C., Dechiara, T. M., and Yancopoulos, G. D. 1995. Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature. 375:235–238.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu, X., Ernfors, P., Wu, H., and Jaenisch, R. 1995 Sensory but not motor neuron deficits in mice lacking NT4 and BDNF. Nature. 375:238–241.PubMedCrossRefGoogle Scholar
  14. 14.
    Ibáñez, C. F., Hallbook, F., Godeau, F., and Persson, H. 1992 Expression of neurotrophin-4 messenger RNA during oogenesis in Xenopus-laevis. Int J Dev Biol. 36:239–245.PubMedGoogle Scholar
  15. 15.
    Berkemeier, L., Winslow, J., Kaplan, D., Nicolics, K., Goeddel, D., and Rosenthal, A. 1991 Neurotropin-5: A novel neurotropic factor tat activates trk and trkB. Neuron. 7:857–866.PubMedCrossRefGoogle Scholar
  16. 16.
    Klein, R., Lamballe, F., Bryant, S. and Barbacid, M. 1992 ThetrkB tyrosine protein kinase is a receptor for neurotrophin-4. Neuron. 8:947–956.PubMedCrossRefGoogle Scholar
  17. 17.
    Ip, N. Y., Stitt, T. N., Tapley, P., Klein, R., Glass, D. J., Fandl, J., Greene, L. A., Barbacid, M., and Yancopoulos, G. D. 1993 Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells. Neuron. 10: 137–149.PubMedCrossRefGoogle Scholar
  18. 18.
    Götz, R., Koster, R., Winkler, C., Raulf, F., Lottspeich, F., Schartl, M., and Thoenen, H. 1994 Neurotrophin-6 is a new member of the nerve growth factor family. Nature. 372:266–269.PubMedCrossRefGoogle Scholar
  19. 19.
    Berkemeier, L. R., Ozcelik, T., Francke, U., and Rosenthal, A. 1992 Human chromosome-19 contains the neurotrophin-5 gene locus and 3 related genes that may encode novel acidic neurotrophins. Somatic Cell and Molecular Genetics. 18:233–245.PubMedCrossRefGoogle Scholar
  20. 20.
    Fandl, J. P., Tobkes, N. J., Mcdonald, N. Q., Hendrickson, W. A., Ryan, T. E., Nigam, S., Acheson, A., Cudny, H., and Panayotatos, N. 1994 Characterization and crystallization of recombinant human neurotrophin-4. J Biol Chem. 269:755–759.PubMedGoogle Scholar
  21. 21.
    Götz, R., Raulf, F., and Schartl, M. 1992. Brain-derived neurotrophic factor is more highly conserved in structure and function than nerve growth factor during vertebrate evolution. J Neurochem. 59:432–442.PubMedCrossRefGoogle Scholar
  22. 22.
    Barde, Y.-A. 1994. Neurotrophic factors: An evolutionary perspective. J. Neurobiol. 25:Google Scholar
  23. 23.
    Ibáñez, C., Ernfors, P., Timmusk, T., Ip, N., Arenas, E., Yancopoulos, G., and Persson, H. 1993. Neurotrophin-4 is a target-derived neurotrophic factor for neurons of the trigeminal ganglion. Development. 117:1345–1353.PubMedGoogle Scholar
  24. 24.
    Laurenzi, M. A., Barbany, G., Timmusk, T., Lindgren, J. A., and Persson, H. 1994 Expression of mRNA encoding enurotrophins and neurotrophin receptors in rat thymus, spleen tissue and immunocompetent cells—regulation of neurotrophin-4 mRNA expression by mitogens and leukotriene b-4. Eur J Biochem. 223: 733–741.PubMedCrossRefGoogle Scholar
  25. 25.
    Neveu, I., Naveihan, P., Baudet, C., Brachet, P., and Metsis, M. 1994 1,25-Dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes. NeuroReport. 6:123–125.CrossRefGoogle Scholar
  26. 26.
    Koliatsos, V. E., Cayouette, M. H., Berkemeier, L. R., Clatterbuck, R. E., Price, D. L., and Rosenthal, A. 1994. Neurotrophin-4/neurotrophin-5 is a trophic factor for mammalian facial motor neurons. Proc Natl Acad Sci USA. 91:3304–3308.PubMedCrossRefGoogle Scholar
  27. 27.
    Caroni, P., Schneider, C., Kiefer, M. C., and Zapf, J. 1994 Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4. J Cell Biol. 125:893–902.PubMedCrossRefGoogle Scholar
  28. 28.
    Ibáñez, C. F. 1995. Neurotrophic factors: from structure-function relationships to designing efficient therapeutics. Trends Biotechnol. 13:217–227.PubMedCrossRefGoogle Scholar
  29. 29.
    Windisch, J. M., Marksteiner, R., Lang, M. E., Auer, B., and Schneider, R. 1995 Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 bind to a single leucine-rich motif of TrkB. Biochemistry. 34:11256–11263.PubMedCrossRefGoogle Scholar
  30. 30.
    Ibáñez, C. F., Ebendal, T., Barbany, G., Murrayrust, 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Davies, A. M., Horton, A., Burton, L. E., Schmelzer, C., Vandlen, R., and Rosenthal, A. 1993 Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. J Neurosci. 13:4961–4967.PubMedGoogle Scholar
  32. 32.
    Zheng, J. L., Stewart, R. R., and Gao, W. Q. 1995 Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity. J Neurosci. 15:5079–5087.PubMedGoogle Scholar
  33. 33.
    Ip, N. Y., Li, Y. P., Yancopoulos, G. D., and Lindsay, R. M. 1993 Cultured hippocampal neurons show responses to BDNF, NT-3, and NT-4, but not NGF. J Neurosci. 13:3394–3405.PubMedGoogle Scholar
  34. 34.
    Friedman, W. J., Ibáñez, C. F., Hallbook, F., Persson, H., Cain L. D., Dreyfus, C. F., and Black, I. B. 1993 Differential actions of neurotrophins in the locuscoeruleus and basal forebrain. Exp Neurol. 119:72–78.PubMedCrossRefGoogle Scholar
  35. 35.
    Hyman, C., Juhasz, M., Jackson, C., Wright, P., Ip, N. Y., and Lindsay, R. M. 1994 Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci. 14:335–347.PubMedGoogle Scholar
  36. 36.
    Hynes, M. A., Poulsen, K., Armanini, M., Berkemeier, L., Phillips, H., and Rosenthal, A. 1994 Neurotrophin-4/5 is a survival factor for embryonic midbrain dopaminergic neurons in enriched cultures. J Neurosci Res. 37:144–154.PubMedCrossRefGoogle Scholar
  37. 37.
    Gao, W. Q., Zheng, J. L., and Karihaloo, M. 1995 Neurotrophin-4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF) act at later stages of cerebellar granule cell differentiation. J Neurosci. 15:2656–2667.PubMedGoogle Scholar
  38. 38.
    Widmer, H. R. and Hefti, F. 1994 Neurotrophin-4/5 promotes survival and differentiation of rat striatal neurons developing in culture. Eur J Neurosci. 6:1669–1679.PubMedCrossRefGoogle Scholar
  39. 39.
    Cabelli, R. J., Hohn, A., and Shatz, C. J. 1995 Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF. Science. 267:1662–1666.PubMedCrossRefGoogle Scholar
  40. 40.
    Altar, C. A., Boylan, C. B., Fritsche, M., Jackson, C., Hyman, C. and Lindsay, R. M. 1994 The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra. Exp Neurol. 130:31–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Sauer, H., Wong, V., and Bjorklund, A. 1995 Brain-derived neurotrophic factor and neurotrophin-4/5 modify neurotransmitter-related gene expression in the 6-hydroxydopamine-lesioned rat striatum. Neuroscience. 65:927–933.PubMedCrossRefGoogle Scholar
  42. 42.
    Arenas, E., Åkerud, P., Wong, V., Boylan, C., Persson, H., Lindsay, R. M. and Altar, C. A. 1996 Effects of BDNF and NT-4/5 on striatonigral GABA neurons in vivo. Eur. J. Neurosci., in press.Google Scholar
  43. 43.
    Ardelt, A. A., Flaris, N. A., and Roth, K. A. 1994. Neurotrophin-4 selectively promotes survival of striatal neurons in organotypic slice culture. Brain Res. 647:340–344.PubMedCrossRefGoogle Scholar
  44. 44.
    Fischer, W., Sirevaag, A., Wiegand, S. J., Lindsay, R. M., and Björklund, A. 1994 Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 91:8607–8611.PubMedCrossRefGoogle Scholar
  45. 45.
    Altar, C. A., Siuciak, J. A., Wright, P., Ip, N. Y., Lindsay, R. M., and Wiegand, S. J. 1994 In situ hybridization of trkB and trkC receptor mRNA in rat forebrain and association with high-affinity binding of [I-125]BDNF, [I-125]NT-4/5 and [I-125]NT-3. Eur J Neurosci. 6:1389–1405.PubMedCrossRefGoogle Scholar
  46. 46.
    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.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee, K. F., Bachman, K., Landis, S., and Jaenisch, R. 1994 Dependence on p75 for innervation of some sympathetic targets. Science. 263:1447–1449.PubMedCrossRefGoogle Scholar
  48. 48.
    Snider, W. D. 1994 Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell. 77:627–638.PubMedCrossRefGoogle Scholar
  49. 49.
    Ernfors, P., Lee, K. F. and Jaenisch, R. 1994 Mice lacking brainderived neurotrophic factor develop with sensory deficits. Nature. 368:147–150.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Carlos F. Ibáñez
    • 1
  1. 1.Department of Medical Biochemistry and Biophysics, Laboratory of Molecular NeurobiologyKarolinska InstituteStockholmSweden

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