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Gene Review

NTF4  -  neurotrophin 4

Homo sapiens

Synonyms: GLC10, GLC1O, NT-4, NT-4/5, NT-5, ...
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Disease relevance of NTF5


Psychiatry related information on NTF5


High impact information on NTF5

  • Many types of neurons in the central nervous system are excited by BDNF or neurotrophin-4/5, an action that has recently been implicated in synaptic plasticity [9].
  • At vanishingly low concentrations, factors of the neurotrophin family (NGF, BDNF, NT3 and NT4/5) can promote neuronal survival or death [10].
  • Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A [11].
  • Heterotopic neurons have the same birth date and phenotype as normal MZ neurons; they are not the result of NT4-induced proliferation or rescue from apoptosis [12].
  • Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4 [12].

Biological context of NTF5

  • In the human, both NTF5 and NTF6 gene loci were mapped to chromosome 19 by Southern analysis of somatic cell hybrid panels [13].
  • Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity [14].
  • We found that acute administration of NT-4/5 to 7-day-old cultures stimulates the hydrolysis of phosphatidylinositol, an event involved in neurotrophin signal transduction [15].
  • Growth of striatal cultures in the presence of NT-4/5 resulted in increased cell survival, as indicated by elevations in cell number, protein content, and a measure of mitochondrial enzyme activity (MTT assay) [15].
  • NT-4/5 transiently supported mouse NGF-dependent trigeminal and jugular neurons at early stages of target field innervation and mouse brain-derived neurotrophic factor (BDNF)-dependent no-dose neurons during the phase of naturally occurring cell death [16].

Anatomical context of NTF5


Associations of NTF5 with chemical compounds

  • NT-4/5 increased GABA uptake and staining intensity in these cultures, as indicated by GABA immunocytochemistry, indicating a trophic action on GABAergic neurons, the predominant neuron type in the striatum [15].
  • This suggests that the autocrine expression of NGF, BDNF and NT-4/5 is up-regulated in prostate epithelial cells following their transformation to an androgen refractory pathology [20].
  • At maximally effective concentrations, BDNF or NT-4 induced robust TrkB tyrosine phosphorylation at 5 min; this progressively declined at 15, 30, and 60 min [21].
  • The NT4 repeated sequence LKTEN was highly homologous with a site conserved in cardiac myosins, the B repeat region peptides were 47% homologous to human cardiac myosin amino acid sequence, and the C3 sequence RRDL was identical to a highly conserved site in skeletal and cardiac myosins [22].
  • Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 all significantly increased levels of substance P after either a 4 h or 20 h incubation in ganglia obtained at stages 33 and 44 [23].

Physical interactions of NTF5

  • RESULTS: We have determined the 2.7 A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain of its high-affinity receptor TrkB (TrkB-d5) [24].
  • Moreover, neutralizing the activity of endogenous NGF with a specific blocking antibody, or antagonizing NGF binding to p75(NTR) by the application of human NT-4/5, reduces the levels of apoptotic cell death in both the sclerotome and the dermamyotome by about 50 and 70%, respectively [25].

Regulatory relationships of NTF5

  • NT-4 was active in promoting the survival of rat TrkB receptor-expressing fibroblasts, but was inactive on embryonic chicken sensory neurons, unlike the other members of the neurotrophin family and in contrast to the reported activities of partially purified NT-4 [5].

Other interactions of NTF5

  • The results suggest that neurotrophins may act as granulocyte-derived effector molecules and that human bone marrow cells may be targets for these compounds, in particular BDNF and NT-4 [19].
  • Transcription of NT-4 was only detected in epithelium and transcription of GDNF only in stroma [26].
  • As a single factor NT-4/5 produced the greatest increase in ChAT activity, but was not additive with any other neurotrophin or CNTF [27].
  • NGF, NT-3 and NT-4 showed no significant differences within surviving neurons or neuropil [28].
  • This occurs in parallel with an increased expression of GFAP suggesting that reactive changes in Muller cells may be responsible for reduced NT4 staining [3].

Analytical, diagnostic and therapeutic context of NTF5

  • We describe the expression and purification of the second Ig-like domain of human TrkB (TrkBIg(2)) and show, using surface plasmon resonance, that this domain is sufficient to bind BDNF and NT-4 with subnanomolar affinity [2].
  • CONCLUSION: NT4 is expressed in inner and outer nuclear layers of normal human retina and its expression is downregulated following laser photocoagulation [3].
  • Northern blot analysis of different tissues from Xenopus showed NT-4 mRNA only in ovary, where it was present at levels over 100-fold higher than those of NGF mRNA in heart [29].
  • Total RNA was extracted from the frozen ovarian samples, and the expression of NT-4/5, BDNF and the TrkB receptor (full length and two truncated isoforms) was investigated by RT-PCR [30].
  • In agreement with the pattern of trk receptor expression, infusion of recombinant human BDNF or NT-4/5 into the vicinity of the axotomized RSNs, between days 7 and 14 after axotomy, fully prevented their atrophy [31].


  1. The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma. Nassenstein, C., Braun, A., Erpenbeck, V.J., Lommatzsch, M., Schmidt, S., Krug, N., Luttmann, W., Renz, H., Virchow, J.C. J. Exp. Med. (2003) [Pubmed]
  2. A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4. Naylor, R.L., Robertson, A.G., Allen, S.J., Sessions, R.B., Clarke, A.R., Mason, G.G., Burston, J.J., Tyler, S.J., Wilcock, G.K., Dawbarn, D. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  3. Laser photocoagulation alters the pattern of staining for neurotrophin-4, GFAP, and CD68 in human retina. Ghazi-Nouri, S.M., Assi, A., Limb, G.A., Scott, R.A., von Bussmann, K., Humphrey, I., Luthert, P.J., Charteris, D.G. The British journal of ophthalmology. (2003) [Pubmed]
  4. Neurotrophins and hyperalgesia. Shu, X.Q., Mendell, L.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  5. Characterization and crystallization of recombinant human neurotrophin-4. Fandl, J.P., Tobkes, N.J., McDonald, N.Q., Hendrickson, W.A., Ryan, T.E., Nigam, S., Acheson, A., Cudny, H., Panayotatos, N. J. Biol. Chem. (1994) [Pubmed]
  6. Serum neurotrophin concentrations in autism and mental retardation: a pilot study. Miyazaki, K., Narita, N., Sakuta, R., Miyahara, T., Naruse, H., Okado, N., Narita, M. Brain Dev. (2004) [Pubmed]
  7. Activity-dependent change in the protein level of brain-derived neurotrophic factor but no change in other neurotrophins in the visual cortex of young and adult ferrets. Ichisaka, S., Katoh-Semba, R., Hata, Y., Ohshima, M., Kameyama, K., Tsumoto, T. Neuroscience (2003) [Pubmed]
  8. Cellular delivery of CNTF but not NT-4/5 prevents degeneration of striatal neurons in a rodent model of Huntington's disease. Emerich, D.F., Bruhn, S., Chu, Y., Kordower, J.H. Cell transplantation. (1998) [Pubmed]
  9. Neurotrophin-evoked depolarization requires the sodium channel Na(V)1.9. Blum, R., Kafitz, K.W., Konnerth, A. Nature (2002) [Pubmed]
  10. The protean actions of neurotrophins and their receptors on the life and death of neurons. Kalb, R. Trends Neurosci. (2005) [Pubmed]
  11. Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors. Kermani, P., Rafii, D., Jin, D.K., Whitlock, P., Schaffer, W., Chiang, A., Vincent, L., Friedrich, M., Shido, K., Hackett, N.R., Crystal, R.G., Rafii, S., Hempstead, B.L. J. Clin. Invest. (2005) [Pubmed]
  12. Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4. Brunstrom, J.E., Gray-Swain, M.R., Osborne, P.A., Pearlman, A.L. Neuron (1997) [Pubmed]
  13. Human chromosome 19 contains the neurotrophin-5 gene locus and three related genes that may encode novel acidic neurotrophins. Berkemeier, L.R., Ozçelik, T., Francke, U., Rosenthal, A. Somat. Cell Mol. Genet. (1992) [Pubmed]
  14. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Ip, N.Y., Ibáñez, C.F., Nye, S.H., McClain, J., Jones, P.F., Gies, D.R., Belluscio, L., Le Beau, M.M., Espinosa, R., Squinto, S.P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  15. Neurotrophin-4/5 promotes survival and differentiation of rat striatal neurons developing in culture. Widmer, H.R., Hefti, F. Eur. J. Neurosci. (1994) [Pubmed]
  16. Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. Davies, A.M., Horton, A., Burton, L.E., Schmelzer, C., Vandlen, R., Rosenthal, A. J. Neurosci. (1993) [Pubmed]
  17. Neurotrophin-4/5 and neurotrophin-3 are present within the human ovarian follicle but appear to have different paracrine/autocrine functions. Seifer, D.B., Feng, B., Shelden, R.M., Chen, S., Dreyfus, C.F. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  18. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Hock, C., Heese, K., Hulette, C., Rosenberg, C., Otten, U. Arch. Neurol. (2000) [Pubmed]
  19. Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells--enhanced neurotrophin-4 expression induced by LTB4. Laurenzi, M.A., Beccari, T., Stenke, L., Sjölinder, M., Stinchi, S., Lindgren, J.A. J. Leukoc. Biol. (1998) [Pubmed]
  20. Molecular characterization of neurotrophin expression and the corresponding tropomyosin receptor kinases (trks) in epithelial and stromal cells of the human prostate. Dalal, R., Djakiew, D. Mol. Cell. Endocrinol. (1997) [Pubmed]
  21. Early BDNF, NT-3, and NT-4 signaling events. Yuen, E.C., Mobley, W.C. Exp. Neurol. (1999) [Pubmed]
  22. Molecular analysis of human cardiac myosin-cross-reactive B- and T-cell epitopes of the group A streptococcal M5 protein. Cunningham, M.W., Antone, S.M., Smart, M., Liu, R., Kosanke, S. Infect. Immun. (1997) [Pubmed]
  23. Differential regulation of substance P by all members of the nerve growth factor family of neurotrophins in avian dorsal root ganglia throughout development. Yao, L., Zhang, D., Bernd, P. Neuroscience (1997) [Pubmed]
  24. Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Banfield, M.J., Naylor, R.L., Robertson, A.G., Allen, S.J., Dawbarn, D., Brady, R.L. Structure (Camb.) (2001) [Pubmed]
  25. Programmed cell death in the developing somites is promoted by nerve growth factor via its p75(NTR) receptor. Cotrina, M.L., González-Hoyuela, M., Barbas, J.A., Rodríguez-Tébar, A. Dev. Biol. (2000) [Pubmed]
  26. Neurotrophic factors in the human cornea. You, L., Kruse, F.E., Völcker, H.E. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  27. Overlapping and additive effects of neurotrophins and CNTF on cultured human spinal cord neurons. Kato, A.C., Lindsay, R.M. Exp. Neurol. (1994) [Pubmed]
  28. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain. Chauhan, N.B., Siegel, G.J., Lee, J.M. J. Chem. Neuroanat. (2001) [Pubmed]
  29. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Hallböök, F., Ibáñez, C.F., Persson, H. Neuron (1991) [Pubmed]
  30. Tyrosine kinase B receptor and its activated neurotrophins in ovaries from human fetuses and adults. Harel, S., Jin, S., Fisch, B., Feldberg, D., Krissi, H., Felz, C., Freimann, S., Tan, S.L., Ao, A., Abir, R. Mol. Hum. Reprod. (2006) [Pubmed]
  31. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal regeneration. Kobayashi, N.R., Fan, D.P., Giehl, K.M., Bedard, A.M., Wiegand, S.J., Tetzlaff, W. J. Neurosci. (1997) [Pubmed]
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