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Gene Review

BDNF  -  brain-derived neurotrophic factor

Homo sapiens

Synonyms: ANON2, Abrineurin, BULN2, Brain-derived neurotrophic factor


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Disease relevance of BDNF

  • Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling [1].
  • BDNF haploinsufficiency is associated with lower serum BDNF and pediatric-onset overweight among individuals with WAGR syndrome  [2].
  • Finally, in 15N neuroblastoma cells, which express BDNF mRNA but do not differentiate in response to RA, RA induced only a truncated form of TrkB [3].
  • In postnatal intestine, BDNF immunoreactivity was primarily localized to enteric ganglion cells, with NT-3 localized to enteric plexuses, intermuscular basal lamina, and along or between circular and longitudinal smooth muscle cells [4].
  • However, grafting of BDNF-producing fibroblasts two days before ischemia significantly and specifically prevented nerve cells from dying in the CA1 area of the ipsilateral hippocampus [5].
  • BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated [6].
  • Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment [7].
  • Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females [8].
  • The purpose of this study is to determine which BDNF transcript is involved in cell survival of the human neuroblastoma cell lines SH-SY-5Y (single-copy MYCN) and SK-N-BE (amplified MYCN) [9].

Psychiatry related information on BDNF


High impact information on BDNF

  • Human BDNF gene contains multiple promoters and up to 10 upstream exons that can each be spliced independently to the major BDNF coding exon to form diverse BDNF transcripts [15] [16]
  • We examined the effects of a Met66 (rs6265) substitution of Val66 in the 5' pro-region of the human BDNF protein [17].
  • These results demonstrate a role for BDNF and its Val66Met polymorphism in human memory and hippocampal function and suggest Met66 exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF [17].
  • Integrate genetics and functional brain imaging by showing that Val66Met in the human brain-derived neurotrophic factor (BDNF) gene is associated with variation in episodic memory ability and in hippocampal neurochemistry and function [18].
  • NGF regulates the expression of a second neurotrophin, brain-derived neurotrophic factor (BDNF), in nociceptors [19].
  • BDNF is released when nociceptors are activated, and it acts as a central modulator of pain [19].

Chemical compound and disease context of BDNF


Biological context of BDNF


Anatomical context of BDNF

  • Activated TrkA receptor levels and the survival of NGF-dependent sensory neurons, but not BDNF-dependent sensory neurons, are directly influenced by Nedd4-2 expression [27].
  • Together, these findings suggest that BDNF may be released from primary sensory nociceptors with activity, particularly in some persistent pain states, and may then increase the excitability of rostrally projecting second-order systems [28].
  • Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner [25].
  • Finally, BDNF is expressed by malignant plasma cells isolated from a subset of patients with MM, as well as by most HMCLs, suggesting a potential role for this neurotrophin axis in autocrine as well as paracrine support of MM [24].
  • Thus, our results show that BDNF is able to up-regulate the expression of TrkB in control and pathological states, and that BDNF prevention of neuronal death following transient forebrain ischemia is associated with increased expression of its specific receptor [5].

Associations of BDNF with chemical compounds

  • Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase [25].
  • BDNF also protected TrkB-expressing NGP and KCNR NB cells from chemotherapeutic agent-induced cell death, and LY294002 inhibited this protection [29].
  • BDNF treatment of high TrkB-expressing TB8 (Tet-) and TB3 (Tet-) cells blocked drug-induced cell death in a dose-dependent manner [29].
  • This domain was cross-linked to BDNF through a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide coupling reaction [30].
  • BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically) [31].
  • Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin [32].
  • These findings suggest that BDNF plays an important role in the susceptibility to schizophrenia and that the (GT)n repeat polymorphism of the BDNF gene may be an independent contributor to the chlorpromazine treatment-sensitive form of schizophrenia [33].
  • This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction [34].

Physical interactions of BDNF

  • These results, obtained from a variety of experimental techniques, highlight the importance of two distinct regions of the extracellular domain of the TRKB receptor in binding BDNF [30].
  • Results obtained with cells transfected with the low-affinity NGF receptor gene indicate that these cells bind BDNF, in addition to NGF, whereas cells before transfection do not [35].
  • Sections dual immunoreacted for BNNF and tyrosine hydroxylase revealed a subpopulation of dopaminergic neurons (approximately 28%) within the pars compacta which contained retrogradely transported BDNF [36].
  • In MPTP-treated marmosets BDNF caused increased ipsilateral striatal [3H]mazindol binding with increased somatic size and staining intensity in GAD-immunoreactive cells and a 10-20% loss of nigral TH-immunoreactive cells with increased GFAP staining [37].
  • When NGF binding to p75NTR was blocked by treating cells with either BDNF or PD90780, and where p75NTR expression was reduced by treating cells with antisense oligonucleotide to p75NTR, the protective effects of NGF were attenuated [38].

Regulatory relationships of BDNF


Other interactions of BDNF


Analytical, diagnostic and therapeutic context of BDNF


  1. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Xu, B., Goulding, E.H., Zang, K., Cepoi, D., Cone, R.D., Jones, K.R., Tecott, L.H., Reichardt, L.F. Nat. Neurosci. (2003) [Pubmed]
  2. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. Han, J.C., Liu, Q.R., Jones, M., Levinn, R.L., Menzie, C.M., Jefferson-George, K.S., Adler-Wailes, D.C., Sanford, E.L., Lacbawan, F.L., Uhl, G.R., Rennert, O.M., Yanovski, J.A. N. Engl. J. Med. (2008) [Pubmed]
  3. Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. Kaplan, D.R., Matsumoto, K., Lucarelli, E., Thiele, C.J. Neuron (1993) [Pubmed]
  4. Localization of neurotrophins and their high-affinity receptors during human enteric nervous system development. Hoehner, J.C., Wester, T., Påhlman, S., Olsen, L. Gastroenterology (1996) [Pubmed]
  5. BDNF up-regulates TrkB protein and prevents the death of CA1 neurons following transient forebrain ischemia. Ferrer, I., Ballabriga, J., Martí, E., Pérez, E., Alberch, J., Arenas, E. Brain Pathol. (1998) [Pubmed]
  6. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Nakamura, K., Martin, K.C., Jackson, J.K., Beppu, K., Woo, C.W., Thiele, C.J. Cancer Res. (2006) [Pubmed]
  7. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Gray, J., Yeo, G.S., Cox, J.J., Morton, J., Adlam, A.L., Keogh, J.M., Yanovski, J.A., El Gharbawy, A., Han, J.C., Tung, Y.C., Hodges, J.R., Raymond, F.L., O'rahilly, S., Farooqi, I.S. Diabetes (2006) [Pubmed]
  8. BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Zhang, X.Y., Zhou, D.F., Wu, G.Y., Cao, L.Y., Tan, Y.L., Haile, C.N., Li, J., Lu, L., Kosten, T.A., Kosten, T.R. Neuropsychopharmacology (2008) [Pubmed]
  9. BDNF splice variants from the second promoter cluster support cell survival of differentiated neuroblastoma upon cytotoxic stress. Baj, G., Gabriele, B., Tongiorgi, E., Enrico, T. J. Cell. Sci. (2009) [Pubmed]
  10. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Phillips, H.S., Hains, J.M., Armanini, M., Laramee, G.R., Johnson, S.A., Winslow, J.W. Neuron (1991) [Pubmed]
  11. Neurotrophins and depression. Altar, C.A. Trends Pharmacol. Sci. (1999) [Pubmed]
  12. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Krebs, M.O., Guillin, O., Bourdell, M.C., Schwartz, J.C., Olie, J.P., Poirier, M.F., Sokoloff, P. Mol. Psychiatry (2000) [Pubmed]
  13. Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Bariohay, B., Lebrun, B., Moyse, E., Jean, A. Endocrinology (2005) [Pubmed]
  14. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Ribasés, M., Gratacòs, M., Fernández-Aranda, F., Bellodi, L., Boni, C., Anderluh, M., Cristina Cavallini, M., Cellini, E., Di Bella, D., Erzegovesi, S., Foulon, C., Gabrovsek, M., Gorwood, P., Hebebrand, J., Hinney, A., Holliday, J., Hu, X., Karwautz, A., Kipman, A., Komel, R., Nacmias, B., Remschmidt, H., Ricca, V., Sorbi, S., Tomori, M., Wagner, G., Treasure, J., Collier, D.A., Estivill, X. Eur. J. Hum. Genet. (2005) [Pubmed]
  15. Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease. Liu, Q.R., Walther, D., Drgon, T., Polesskaya, O., Lesnick, T.G., Strain, K.J., de Andrade, M., Bower, J.H., Maraganore, D.M., Uhl, G.R. Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2005) [Pubmed]
  16. Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Pruunsild, P., Kazantseva, A., Aid, T., Palm, K., Timmusk, T. Genomics. (2007) [Pubmed]
  17. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E., Kolachana, B.S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B., Weinberger, D.R. Cell (2003) [Pubmed]
  18. Visualizing genetic influences on human brain functions. Gabrieli, J.D., Preston, A.R. Cell (2003) [Pubmed]
  19. Neurotrophins: mediators and modulators of pain. Pezet, S., McMahon, S.B. Annu. Rev. Neurosci. (2006) [Pubmed]
  20. Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment. Edsjö, A., Lavenius, E., Nilsson, H., Hoehner, J.C., Simonsson, P., Culp, L.A., Martinsson, T., Larsson, C., Påhlman, S. Lab. Invest. (2003) [Pubmed]
  21. Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Cheng, C.Y., Hong, C.J., Yu, Y.W., Chen, T.J., Wu, H.C., Tsai, S.J. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  22. Nicotine regulates SH-SY5Y neuroblastoma cell proliferation through the release of brain-derived neurotrophic factor. Serres, F., Carney, S.L. Brain Res. (2006) [Pubmed]
  23. Neurotrophin trafficking by anterograde transport. Altar, C.A., DiStefano, P.S. Trends Neurosci. (1998) [Pubmed]
  24. A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Pearse, R.N., Swendeman, S.L., Li, Y., Rafii, D., Hempstead, B.L. Blood (2005) [Pubmed]
  25. Expression and function of TRK-B and BDNF in human neuroblastomas. Nakagawara, A., Azar, C.G., Scavarda, N.J., Brodeur, G.M. Mol. Cell. Biol. (1994) [Pubmed]
  26. Neurotrophin secretion: current facts and future prospects. Lessmann, V., Gottmann, K., Malcangio, M. Prog. Neurobiol. (2003) [Pubmed]
  27. Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Arévalo, J.C., Waite, J., Rajagopal, R., Beyna, M., Chen, Z.Y., Lee, F.S., Chao, M.V. Neuron (2006) [Pubmed]
  28. Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Thompson, S.W., Bennett, D.L., Kerr, B.J., Bradbury, E.J., McMahon, S.B. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  29. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3'-kinase pathway. Jaboin, J., Kim, C.J., Kaplan, D.R., Thiele, C.J. Cancer Res. (2002) [Pubmed]
  30. Interactions between brain-derived neurotrophic factor and the TRKB receptor. Identification of two ligand binding domains in soluble TRKB by affinity separation and chemical cross-linking. Haniu, M., Montestruque, S., Bures, E.J., Talvenheimo, J., Toso, R., Lewis-Sandy, S., Welcher, A.A., Rohde, M.F. J. Biol. Chem. (1997) [Pubmed]
  31. Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Kent, L., Green, E., Hawi, Z., Kirley, A., Dudbridge, F., Lowe, N., Raybould, R., Langley, K., Bray, N., Fitzgerald, M., Owen, M.J., O'Donovan, M.C., Gill, M., Thapar, A., Craddock, N. Mol. Psychiatry (2005) [Pubmed]
  32. Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein. Calabrese, F., Molteni, R., Maj, P.F., Cattaneo, A., Gennarelli, M., Racagni, G., Riva, M.A. Neuropsychopharmacology (2007) [Pubmed]
  33. BDNF gene is a genetic risk factor for schizophrenia and is related to the chlorpromazine-induced extrapyramidal syndrome in the Chinese population. Xu, M.Q., St Clair, D., Feng, G.Y., Lin, Z.G., He, G., Li, X., He, L. Pharmacogenet. Genomics (2008) [Pubmed]
  34. Ethanol-BDNF interactions: still more questions than answers. Davis, M.I. Pharmacol. Ther. (2008) [Pubmed]
  35. Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Rodriguez-Tébar, A., Dechant, G., Barde, Y.A. Neuron (1990) [Pubmed]
  36. Intrastriatal infusions of brain-derived neurotrophic factor: retrograde transport and colocalization with dopamine containing substantia nigra neurons in rat. Mufson, E.J., Kroin, J.S., Sobreviela, T., Burke, M.A., Kordower, J.H., Penn, R.D., Miller, J.A. Exp. Neurol. (1994) [Pubmed]
  37. Chronic supranigral infusion of BDNF in normal and MPTP-treated common marmosets. Pearce, R.K., Costa, S., Jenner, P., Marsden, C.D. Journal of neural transmission (Vienna, Austria : 1996) (1999) [Pubmed]
  38. The common neurotrophin receptor p75NTR enhances the ability of PC12 cells to resist oxidative stress by a trkA-dependent mechanism. Wang, W., Dow, K.E., Riopelle, R.J., Ross, G.M. Neurotoxicity research. (2001) [Pubmed]
  39. The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. Easton, J.B., Royer, A.R., Middlemas, D.S. J. Neurochem. (2006) [Pubmed]
  40. Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells. Holback, S., Adlerz, L., Iverfeldt, K. J. Neurochem. (2005) [Pubmed]
  41. Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity. Gray, J., Yeo, G., Hung, C., Keogh, J., Clayton, P., Banerjee, K., McAulay, A., O'rahilly, S., Farooqi, I.S. International journal of obesity (2005) (2007) [Pubmed]
  42. The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway. Traver, S., Marien, M., Martin, E., Hirsch, E.C., Michel, P.P. Mol. Pharmacol. (2006) [Pubmed]
  43. Resistance to chemotherapy mediated by TrkB in neuroblastomas. Ho, R., Eggert, A., Hishiki, T., Minturn, J.E., Ikegaki, N., Foster, P., Camoratto, A.M., Evans, A.E., Brodeur, G.M. Cancer Res. (2002) [Pubmed]
  44. Comparison of the biophysical characteristics of human brain-derived neurotrophic factor, neurotrophin-3, and nerve growth factor. Narhi, L.O., Rosenfeld, R., Talvenheimo, J., Prestrelski, S.J., Arakawa, T., Lary, J.W., Kolvenbach, C.G., Hecht, R., Boone, T., Miller, J.A. J. Biol. Chem. (1993) [Pubmed]
  45. MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients. Molnar, M., Potkin, S.G., Bunney, W.E., Jones, E.G. Biol. Psychiatry (2003) [Pubmed]
  46. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Mufson, E.J., Kroin, J.S., Sendera, T.J., Sobreviela, T. Prog. Neurobiol. (1999) [Pubmed]
  47. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. Mowla, S.J., Farhadi, H.F., Pareek, S., Atwal, J.K., Morris, S.J., Seidah, N.G., Murphy, R.A. J. Biol. Chem. (2001) [Pubmed]
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