Abstract
Neurotrophins (NTs) are members of a neuronal growth factor protein family whose action is mediated by the tropomyosin receptor kinase (TRK) receptor family receptors and the p75 NT receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor family. Although NTs were first discovered in neurons, recent studies have suggested that NTs and their receptors are expressed in various types of stem cells mediating pivotal signaling events in stem cell biology. The concept of stem cell therapy has already attracted much attention as a potential strategy for the treatment of neurodegenerative diseases (NDs). Strikingly, NTs, proNTs, and their receptors are gaining interest as key regulators of stem cells differentiation, survival, self-renewal, plasticity, and migration. In this review, we elaborate the recent progress in understanding of NTs and their action on various stem cells. First, we provide current knowledge of NTs, proNTs, and their receptor isoforms and signaling pathways. Subsequently, we describe recent advances in the understanding of NT activities in various stem cells and their role in NDs, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD). Finally, we compile the implications of NTs and stem cells from a clinical perspective and discuss the challenges with regard to transplantation therapy for treatment of AD and PD.
This is a preview of subscription content, access via your institution.
References
Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276(16):12660–12666. doi:10.1074/jbc.M008104200
Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361(1473):1545–1564. doi:10.1098/rstb.2006.1894
Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14(1):7–23. doi:10.1038/nrn3379
Edelmann E, Cepeda-Prado E, Franck M, Lichtenecker P, Brigadski T, Lessmann V (2015) Theta burst firing recruits BDNF release and signaling in postsynaptic CA1 neurons in spike-timing-dependent LTP. Neuron 86(4):1041–1054. doi:10.1016/j.neuron.2015.04.007
Cohen S, Levi-Montalcini R, Hamburger V (1954) A nerve growth-stimulating factor isolated from sarcom as 37 and 180. Proc Natl Acad Sci U S A 40(10):1014–1018
Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69(5):341–374. doi:10.1016/S0301-0082(03)00019-4
Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237(4819):1154–1162
Arevalo JC, Wu SH (2006) Neurotrophin signaling: many exciting surprises! Cell Mol Life Sci 63(13):1523–1537. doi:10.1007/s00018-006-6010-1
Hempstead BL (2014) Deciphering proneurotrophin actions. Handb Exp Pharmacol 220:17–32. doi:10.1007/978-3-642-45106-5_2
Nykjaer A, Willnow TE (2012) Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci 35(4):261–270. doi:10.1016/j.tins.2012.01.003
Willnow TE, Petersen CM, Nykjaer A (2008) VPS10P-domain receptors—regulators of neuronal viability and function. Nat Rev Neurosci 9(12):899–909. doi:10.1038/nrn2516
Gotz R, Koster R, Winkler C, Raulf F, Lottspeich F, Schartl M, Thoenen H (1994) Neurotrophin-6 is a new member of the nerve growth factor family. Nature 372(6503):266–269. doi:10.1038/372266a0
Lai KO, Fu WY, Ip FC, Ip NY (1998) Cloning and expression of a novel neurotrophin, NT-7, from carp. Mol Cell Neurosci 11(1-2):64–76. doi:10.1006/mcne.1998.0666
Nilsson AS, Fainzilber M, Falck P, Ibanez CF (1998) Neurotrophin-7: a novel member of the neurotrophin family from the zebrafish. FEBS Lett 424(3):285–290. doi:10.1016/S0014-5793(98)00192-6
Berkemeier LR, Ozcelik T, Francke U, Rosenthal A (1992) Human chromosome 19 contains the neurotrophin-5 gene locus and three related genes that may encode novel acidic neurotrophins. Somat Cell Mol Genet 18(3):233–245. doi:10.1007/BF01233860
Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A 78(12):7634–7638
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147
Klimanskaya I, Rosenthal N, Lanza R (2008) Derive and conquer: sourcing and differentiating stem cells for therapeutic applications. Nat Rev Drug Discov 7(2):131–142. doi:10.1038/nrd2403
Goodell MA, Nguyen H, Shroyer N (2015) Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nat Rev Mol Cell Biol 16(5):299–309. doi:10.1038/nrm3980
Wobus AM, Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85(2):635–678. doi:10.1152/physrev.00054.2003
Zhu Z, Huangfu D (2013) Human pluripotent stem cells: an emerging model in developmental biology. Development 140(4):705–717. doi:10.1242/dev.086165
Rookmaaker MB, Schutgens F, Verhaar MC, Clevers H (2015) Development and application of human adult stem or progenitor cell organoids. Nat Rev Nephrol 11(9):546–554. doi:10.1038/nrneph.2015.118
Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66(9):4553–4557. doi:10.1158/0008-5472.CAN-05-3986
Lotem J, Sachs L (2006) Epigenetics and the plasticity of differentiation in normal and cancer stem cells. Oncogene 25(59):7663–7672. doi:10.1038/sj.onc.1209816
Okita K, Yamanaka S (2011) Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci 366(1575):2198–2207. doi:10.1098/rstb.2011.0016
Yamanaka S (2012) Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10(6):678–684. doi:10.1016/j.stem.2012.05.005
Tomellini E, Lagadec C, Polakowska R, Le Bourhis X (2014) Role of p75 neurotrophin receptor in stem cell biology: more than just a marker. Cell Mol Life Sci 71(13):2467–2481. doi:10.1007/s00018-014-1564-9
Lu P, Jones LL, Snyder EY, Tuszynski MH (2003) Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181(2):115–129. doi:10.1016/S0014-4886(03)00037-2
Pyle AD, Lock LF, Donovan PJ (2006) Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnol 24(3):344–350. doi:10.1038/nbt1189
Levi-Montalcini R, Hamburger V (1953) A diffusible agent of mouse sarcoma, producing hyperplasia of sympathetic ganglia and hyperneurotization of viscera in the chick embryo. J Exp Zool 123(2):233–287. doi:10.1002/jez.1401230203
Cohen S, Levi-Montalcini R (1956) A nerve growth-stimulating factor isolated from snake venom. Proc Natl Acad Sci U S A 42(9):571–574
Tischler AS, Riseberg JC, Hardenbrook MA, Cherington V (1993) Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro. J Neurosci 13(4):1533–1542
Misko TP, Radeke MJ, Shooter EM (1987) Nerve growth factor in neuronal development and maintenance. J Exp Biol 132:177–190
Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24:1217–1281. doi:10.1146/annurev.neuro.24.1.1217
Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA (1995) Nerve growth factor in Alzheimer’s disease: increased levels throughout the brain coupled with declines in nucleus basalis. J Neurosci 15(9):6213–6221
Lorigados Pedre L, Pavon Fuentes N, Alvarez Gonzalez L, McRae A, Serrano Sanchez T, Blanco Lescano L, Macias Gonzalez R (2002) Nerve growth factor levels in Parkinson disease and experimental parkinsonian rats. Brain Res 952(1):122–127. doi:10.1016/S0006-8993(02)03222-5
Shamini Ayyadhury BSP, Klaus Heese BSP (2007) Neurotrophins—more than neurotrophic. Curr Immunol Rev 3(3):189–215. doi:10.2174/157339507781483504
Heese K, Inoue N, Sawada T (2006) NF-kappaB regulates B-cell-derived nerve growth factor expression. Cell Mol Immunol 3(1):63–66
Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L, Leon A (1996) Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 19(11):514–520. doi:10.1016/S0166-2236(96)10058-8
Indo Y (2014) Neurobiology of pain, interoception and emotional response: lessons from nerve growth factor-dependent neurons. Eur J Neurosci 39(3):375–391. doi:10.1111/ejn.12448
Lewin GR, Nykjaer A (2014) Pro-neurotrophins, sortilin, and nociception. Eur J Neurosci 39(3):363–374. doi:10.1111/ejn.12466
Torcia M, Bracci-Laudiero L, Lucibello M et al (1996) Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 85(3):345–356. doi:10.1016/S0092-8674(00)81113-7
Einarsdottir E, Carlsson A, Minde J et al (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 13(8):799–805. doi:10.1093/hmg/ddh096
Hallbook F (1999) Evolution of the vertebrate neurotrophin and Trk receptor gene families. Curr Opin Neurobiol 9(5):616–621. doi:10.1016/S0959-4388(99)00011-2
Ullrich A, Gray A, Berman C, Dull TJ (1983) Human beta-nerve growth factor gene sequence highly homologous to that of mouse. Nature 303(5920):821–825
Fahnestock M, Yu G, Coughlin MD (2004) ProNGF: a neurotrophic or an apoptotic molecule? Prog Brain Res 146:101–110. doi:10.1016/S0079-6123(03)46007-X
Darling TL, Petrides PE, Beguin P, Frey P, Shooter EM, Selby M, Rutter WJ (1983) The biosynthesis and processing of proteins in the mouse 7S nerve growth factor complex. Cold Spring Harb Symp Quant Biol 48(Pt 1):427–434
Garzon D, Yu G, Fahnestock M (2004) A new brain-derived neurotrophic factor transcript and decrease inbrain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. J Neurochem 82(5):1058–1064. doi:10.1046/j.1471-4159.2002.01030.x
Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 379(3):247–250
Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294(5548):1945–1948. doi:10.1126/science.1065057
Fahnestock M, Michalski B, Xu B, Coughlin MD (2001) The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol Cell Neurosci 18(2):210–220. doi:10.1006/mcne.2001.1016
Yepes M, Lawrence DA (2004) Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? Trends Cardiovasc Med 14(5):173–180. doi:10.1016/j.tcm.2004.03.004
Iulita MF, Cuello AC (2014) Nerve growth factor metabolic dysfunction in Alzheimer’s disease and Down syndrome. Trends Pharmacol Sci 35(7):338–348. doi:10.1016/j.tips.2014.04.010
Miranda E, Lomas DA (2006) Neuroserpin: a serpin to think about. Cell Mol Life Sci 63(6):709–722. doi:10.1007/s00018-005-5077-4
Bradshaw RA, Murray-Rust J, Ibanez CF, McDonald NQ, Lapatto R, Blundell TL (1994) Nerve growth factor: structure/function relationships. Protein Sci 3(11):1901–1913. doi:10.1002/pro.5560031102
Bax B, Blundell TL, Murray-Rust J, McDonald NQ (1997) Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins. Structure 5(10):1275–1285. doi:10.1016/S0969-2126(97)00280-3
Freund-Michel V, Frossard N (2008) The nerve growth factor and its receptors in airway inflammatory diseases. Pharmacol Ther 117(1):52–76. doi:10.1016/j.pharmthera.2007.07.003
Eibl JK, Strasser BC, Ross GM (2012) Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int 61(8):1266–1275. doi:10.1016/j.neuint.2012.10.008
Robinson RC, Radziejewski C, Stuart DI, Jones EY (1995) Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer. Biochemistry 34(13):4139–4146
Feng D, Kim T, Ozkan E, Light M, Torkin R, Teng KK, Hempstead BL, Garcia KC (2010) Molecular and structural insight into proNGF engagement of p75NTR and sortilin. J Mol Biol 396(4):967–984. doi:10.1016/j.jmb.2009.12.030
Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1(5):549–553
Barde YA, Davies AM, Johnson JE, Lindsay RM, Thoenen H (1987) Brain derived neurotrophic factor. Prog Brain Res 71:185–189
Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341(6238):149–152. doi:10.1038/341149a0
Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 70(5):271–288. doi:10.1002/dneu.20774
Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10(3):209–219. doi:10.1038/nrd3366
Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7(4):276–285. doi:10.2174/157015909790031210
Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5(6):311–322. doi:10.1038/nrneurol.2009.54
Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10(4):345–352. doi:10.1038/sj.mp.4001637
Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R (2014) Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci 8:430. doi:10.3389/fncel.2014.00430
Prakash YS, Martin RJ (2014) Brain-derived neurotrophic factor in the airways. Pharmacol Ther 143(1):74–86. doi:10.1016/j.pharmthera.2014.02.006
Lee DH, Geyer E, Flach AC, Jung K, Gold R, Flugel A, Linker RA, Luhder F (2012) Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol 123(2):247–258. doi:10.1007/s00401-011-0890-3
Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90(3):397–406. doi:10.1016/j.ygeno.2007.05.004
Negro A, Tavella A, Grandi C, Skaper SD (1994) Production and characterization of recombinant rat brain-derived neurotrophic factor and neurotrophin-3 from insect cells. J Neurochem 62(2):471–478
Harte-Hargrove LC, Maclusky NJ, Scharfman HE (2013) Brain-derived neurotrophic factor-estrogen interactions in the hippocampal mossy fiber pathway: implications for normal brain function and disease. Neuroscience 239:46–66. doi:10.1016/j.neuroscience.2012.12.029
Mowla SJ, Pareek S, Farhadi HF et al (1999) Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci 19(6):2069–2080
Faria RS, Sartori CR, Canova F, Ferrari EA (2013) Classical aversive conditioning induces increased expression of mature-BDNF in the hippocampus and amygdala of pigeons. Neuroscience 255:122–133. doi:10.1016/j.neuroscience.2013.09.054
Carlino D, De Vanna M, Tongiorgi E (2013) Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions? Neuroscientist 19(4):345–353. doi:10.1177/1073858412469444
Nagappan G, Zaitsev E, Senatorov VV Jr, Yang J, Hempstead BL, Lu B (2009) Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc Natl Acad Sci U S A 106(4):1267–1272. doi:10.1073/pnas.0807322106
Pang PT, Teng HK, Zaitsev E et al (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306(5695):487–491. doi:10.1126/science.1100135
Robinson RC, Radziejewski C, Spraggon G et al (1999) The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci 8(12):2589–2597. doi:10.1110/ps.8.12.2589
Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM, Yancopoulos GD (1990) Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 247(4949 Pt 1):1446–1451
Chalazonitis A (1996) Neurotrophin-3 as an essential signal for the developing nervous system. Mol Neurobiol 12(1):39–53. doi:10.1007/BF02740746
Maisonpierre PC, Le Beau MM, Espinosa R 3rd et al (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10(3):558–568
Chalazonitis A (2004) Neurotrophin-3 in the development of the enteric nervous system. Prog Brain Res 146:243–263. doi:10.1016/S0079-6123(03)46016-0
Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R (1999) Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci 2(2):115–117. doi:10.1038/5669
Lykissas MG, Batistatou AK, Charalabopoulos KA, Beris AE (2007) The role of neurotrophins in axonal growth, guidance, and regeneration. Curr Neurovasc Res 4(2):143–151
Roh J, Muelleman T, Tawfik O, Thomas SM (2015) Perineural growth in head and neck squamous cell carcinoma: a review. Oral Oncol 51(1):16–23. doi:10.1016/j.oraloncology.2014.10.004
Tauszig-Delamasure S, Bouzas-Rodriguez J (2011) Targeting neurotrophin-3 and its dependence receptor tyrosine kinase receptor C: a new antitumoral strategy. Expert Opin Ther Targets 15(7):847–858. doi:10.1517/14728222.2011.575361
Yano H, Torkin R, Martin LA, Chao MV, Teng KK (2009) Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing. J Neurosci 29(47):14790–14802. doi:10.1523/JNEUROSCI.2059-09.2009
Farhadi HF, Mowla SJ, Petrecca K, Morris SJ, Seidah NG, Murphy RA (2000) Neurotrophin-3 sorts to the constitutive secretory pathway of hippocampal neurons and is diverted to the regulated secretory pathway by coexpression with brain-derived neurotrophic factor. J Neurosci 20(11):4059–4068
Butte MJ, Hwang PK, Mobley WC, Fletterick RJ (1998) Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors. Biochemistry 37(48):16846–16852. doi:10.1021/bi981254o
Ibanez CF (1996) Neurotrophin-4: the odd one out in the neurotrophin family. Neurochem Res 21(7):787–793
Berkemeier LR, Winslow JW, Kaplan DR, Nikolics K, Goeddel DV, Rosenthal A (1991) Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron 7(5):857–866
Koliatsos VE, Cayouette MH, Berkemeier LR, Clatterbuck RE, Price DL, Rosenthal A (1994) Neurotrophin 4/5 is a trophic factor for mammalian facial motor neurons. Proc Natl Acad Sci U S A 91(8):3304–3308
Zheng JL, Stewart RR, Gao WQ (1995) Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity. J Neurosci 15(7 Pt 2):5079–5087
Cohen A, Bray GM, Aguayo AJ (1994) Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. J Neurobiol 25(8):953–959. doi:10.1002/neu.480250805
Hondermarck H (2012) Neurotrophins and their receptors in breast cancer. Cytokine Growth Factor Rev 23(6):357–365. doi:10.1016/j.cytogfr.2012.06.004
Szczepankiewicz A, Rachel M, Sobkowiak P, Kycler Z, Wojsyk-Banaszak I, Schoneich N, Skibinska M, Breborowicz A (2012) Serum neurotrophin-3 and neurotrophin-4 levels are associated with asthma severity in children. Eur Respir J 39(4):1035–1037. doi:10.1183/09031936.00136611
Aven L, Paez-Cortez J, Achey R, Krishnan R, Ram-Mohan S, Cruikshank WW, Fine A, Ai X (2014) An NT4/TrkB-dependent increase in innervation links early-life allergen exposure to persistent airway hyperreactivity. FASEB J 28(2):897–907. doi:10.1096/fj.13-238212
Grewe M, Vogelsang K, Ruzicka T, Stege H, Krutmann J (2000) Neurotrophin-4 production by human epidermal keratinocytes: increased expression in atopic dermatitis. J Investig Dermatol 114(6):1108–1112. doi:10.1046/j.1523-1747.2000.00974.x
Kanda N, Koike S, Watanabe S (2005) Prostaglandin E2 enhances neurotrophin-4 production via EP3 receptor in human keratinocytes. J Pharmacol Exp Ther 315(2):796–804. doi:10.1124/jpet.105.091645
Yoshizaki K, Yamamoto S, Yamada A et al (2008) Neurotrophic factor neurotrophin-4 regulates ameloblastin expression via full-length TrkB. J Biol Chem 283(6):3385–3391. doi:10.1074/jbc.M704913200
Wiesmann C, Ultsch MH, Bass SH, de Vos AM (1999) Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401(6749):184–188. doi:10.1038/43705
Greco A, Villa R, Pierotti MA (1996) Genomic organization of the human NTRK1 gene. Oncogene 13(11):2463–2466
Barker PA, Lomen-Hoerth C, Gensch EM, Meakin SO, Glass DJ, Shooter EM (1993) Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem 268(20):15150–15157
Tacconelli A, Farina AR, Cappabianca L et al (2004) TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6(4):347–360. doi:10.1016/j.ccr.2004.09.011
Meakin SO, Gryz EA, MacDonald JI (1997) A kinase insert isoform of rat TrkA supports nerve growth factor-dependent cell survival but not neurite outgrowth. J Neurochem 69(3):954–967
Dubus P, Parrens M, El-Mokhtari Y, Ferrer J, Groppi A, Merlio JP (2000) Identification of novel trkA variants with deletions in leucine-rich motifs of the extracellular domain. J Neuroimmunol 107(1):42–49
Jullien J, Guili V, Reichardt LF, Rudkin BB (2002) Molecular kinetics of nerve growth factor receptor trafficking and activation. J Biol Chem 277(41):38700–38708. doi:10.1074/jbc.M202348200
Zhou J, Valletta JS, Grimes ML, Mobley WC (1995) Multiple levels for regulation of TrkA in PC12 cells by nerve growth factor. J Neurochem 65(3):1146–1156
Marlin MC, Li G (2015) Biogenesis and function of the NGF/TrkA signaling endosome. Int Rev Cell Mol Biol 314:239–257. doi:10.1016/bs.ircmb.2014.10.002
Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM (1999) Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J Mol Biol 290(1):149–159. doi:10.1006/jmbi.1999.2816
Urfer R, Tsoulfas P, O’Connell L, Hongo JA, Zhao W, Presta LG (1998) High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273(10):5829–5840
Bertrand T, Kothe M, Liu J et al (2012) The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J Mol Biol 423(3):439–453. doi:10.1016/j.jmb.2012.08.002
Nikoletopoulou V, Lickert H, Frade JM, Rencurel C, Giallonardo P, Zhang L, Bibel M, Barde YA (2010) Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467(7311):59–63. doi:10.1038/nature09336
Soppet D, Escandon E, Maragos J et al (1991) The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65(5):895–903
Slaugenhaupt SA, Blumenfeld A, Liebert CB et al (1995) The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene. Genomics 25(3):730–732
Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736. doi:10.1146/annurev.neuro.24.1.677
Ninkina N, Grashchuck M, Buchman VL, Davies AM (1997) TrkB variants with deletions in the leucine-rich motifs of the extracellular domain. J Biol Chem 272(20):13019–13025
Baxter GT, Radeke MJ, Kuo RC et al (1997) Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J Neurosci 17(8):2683–2690
Stoilov P, Castren E, Stamm S (2002) Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem Biophys Res Commun 290(3):1054–1065. doi:10.1006/bbrc.2001.6301
Forooghian F, Kojic L, Gu Q, Prasad SS (2001) Identification of a novel truncated isoform of trkB in the kitten primary visual cortex. J Mol Neurosci 17(1):81–88. doi:10.1385/JMN:17:1:81
Barbacid M (1995) Neurotrophic factors and their receptors. Curr Opin Cell Biol 7(2):148–155
Feng Y, Vetro A, Kiss E et al (2008) Association of the neurotrophic tyrosine kinase receptor 3 (NTRK3) gene and childhood-onset mood disorders. Am J Psychiatry 165(5):610–616. doi:10.1176/appi.ajp.2007.07050805
Lamballe F, Klein R, Barbacid M (1991) trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66(5):967–979
Lamballe F, Tapley P, Barbacid M (1993) trkC encodes multiple neurotrophin-3 receptors with distinct biological properties and substrate specificities. EMBO J 12(8):3083–3094
Valenzuela DM, Maisonpierre PC, Glass DJ et al (1993) Alternative forms of rat TrkC with different functional capabilities. Neuron 10(5):963–974
Tsoulfas P, Soppet D, Escandon E, Tessarollo L, Mendoza-Ramirez JL, Rosenthal A, Nikolics K, Parada LF (1993) The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells. Neuron 10(5):975–990
Radeke MJ, Misko TP, Hsu C, Herzenberg LA, Shooter EM (1987) Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 325(6105):593–597. doi:10.1038/325593a0
Huebner K, Isobe M, Chao M et al (1986) The nerve growth-factor receptor gene is at human-chromosome region 17q12-17q22, distal to the chromosome-17 breakpoint in acute leukemias. Proc Natl Acad Sci U S A 83(5):1403–1407. doi:10.1073/pnas.83.5.1403
Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309. doi:10.1038/nrn1078
Kraemer BR, Yoon SO, Carter BD (2014) The biological functions and signaling mechanisms of the p75 neurotrophin receptor. Handb Exp Pharmacol 220:121–164. doi:10.1007/978-3-642-45106-5_6
Barrett GL (2000) The p75 neurotrophin receptor and neuronal apoptosis. Prog Neurobiol 61(2):205–229. doi:10.1016/S0301-0082(99)00056-8
von Schack D, Casademunt E, Schweigreiter R, Meyer M, Bibel M, Dechant G (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4(10):977–978. doi:10.1038/nn730
Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, 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(5):737–749
Poser R, Dokter M, von Bohlen Und Halbach V, Berger SM, Busch R, Baldus M, Unsicker K, von Bohlen Und Halbach O (2015) Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 9:63. doi:10.3389/fnana.2015.00063
Sabry MA, Fares M, Folkesson R, Al-Ramadan M, Alabkal J, Al-Kafaji G, Hassan M (2016) Commentary: Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 10:14. doi:10.3389/fnana.2016.00014
Langevin C, Jaaro H, Bressanelli S, Fainzilber M, Tuffereau C (2002) Rabies virus glycoprotein (RVG) is a trimeric ligand for the N-terminal cysteine-rich domain of the mammalian p75 neurotrophin receptor. J Biol Chem 277(40):37655–37662. doi:10.1074/jbc.M201374200
Dechant G, Barde YA (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci 5(11):1131–1136. doi:10.1038/nn1102-1131
Nykjaer A, Lee R, Teng KK et al (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427(6977):843–848. doi:10.1038/nature02319
Grob PM, Ross AH, Koprowski H, Bothwell M (1985) Characterization of the human melanoma nerve growth factor receptor. J Biol Chem 260(13):8044–8049
Gong Y, Cao P, Yu HJ, Jiang T (2008) Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature 454(7205):789–793. doi:10.1038/nature07089
Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35(1):24–35. doi:10.1016/j.tins.2011.06.007
Skaper SD (2012) The neurotrophin family of neurotrophic factors: an overview. Methods Mol Biol 846:1–12. doi:10.1007/978-1-61779-536-7_1
Deinhardt K, Chao MV (2014) Trk receptors. Handb Exp Pharmacol 220:103–119. doi:10.1007/978-3-642-45106-5_5
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. doi:10.1038/378785a0
Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci U S A 97(20):11074–11079. doi:10.1073/pnas.190297597
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65(4):391–426
Vaillant AR, Mazzoni I, Tudan C, Boudreau M, Kaplan DR, Miller FD (1999) Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival. J Cell Biol 146(5):955–966
Besset V, Scott RP, Ibanez CF (2000) Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J Biol Chem 275(50):39159–39166. doi:10.1074/jbc.M006908200
Auer M, Hausott B, Klimaschewski L (2011) Rho GTPases as regulators of morphological neuroplasticity. Ann Anat 193(4):259–266. doi:10.1016/j.aanat.2011.02.015
Hall A, Lalli G (2010) Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harb Perspect Biol 2(2):a001818. doi:10.1101/cshperspect.a001818
Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19(1):1–49. doi:10.1101/gad.1256405
Khodosevich K, Monyer H (2010) Signaling involved in neurite outgrowth of postnatally born subventricular zone neurons in vitro. BMC Neurosci 11:18. doi:10.1186/1471-2202-11-18
Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7(9):923–929. doi:10.1038/nn1295
Schwartz M (2004) Rho signalling at a glance. J Cell Sci 117(Pt 23):5457–5458. doi:10.1242/jcs.01582
Chen C, Wirth A, Ponimaskin E (2012) Cdc42: an important regulator of neuronal morphology. Int J Biochem Cell Biol 44(3):447–451. doi:10.1016/j.biocel.2011.11.022
Azzarelli R, Kerloch T, Pacary E (2014) Regulation of cerebral cortex development by Rho GTPases: insights from in vivo studies. Front Cell Neurosci 8:445. doi:10.3389/fncel.2014.00445
Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, Hoshino M, Kaibuchi K (2005) PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7(3):270–277. doi:10.1038/ncb1227
Shepherd TR, Hard RL, Murray AM, Pei D, Fuentes EJ (2011) Distinct ligand specificity of the Tiam1 and Tiam2 PDZ domains. Biochemistry 50(8):1296–1308. doi:10.1021/bi1013613
Watabe-Uchida M, John KA, Janas JA, Newey SE, Van Aelst L (2006) The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18. Neuron 51(6):727–739. doi:10.1016/j.neuron.2006.07.020
Ng J, Luo L (2004) Rho GTPases regulate axon growth through convergent and divergent signaling pathways. Neuron 44(5):779–793. doi:10.1016/j.neuron.2004.11.014
Yamaguchi Y, Katoh H, Yasui H, Mori K, Negishi M (2001) RhoA inhibits the nerve growth factor-induced Rac1 activation through Rho-associated kinase-dependent pathway. J Biol Chem 276(22):18977–18983. doi:10.1074/jbc.M100254200
Nusser N, Gosmanova E, Zheng Y, Tigyi G (2002) Nerve growth factor signals through TrkA, phosphatidylinositol 3-kinase, and Rac1 to inactivate RhoA during the initiation of neuronal differentiation of PC12 cells. J Biol Chem 277(39):35840–35846. doi:10.1074/jbc.M203617200
Arakawa Y, Bito H, Furuyashiki T et al (2003) Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons. J Cell Biol 161(2):381–391. doi:10.1083/jcb.200210149
Shirazi Fard S, Kele J, Vilar M, Paratcha G, Ledda F (2010) Tiam1 as a signaling mediator of nerve growth factor-dependent neurite outgrowth. PLoS One 5(3), e9647. doi:10.1371/journal.pone.0009647
Zhou P, Porcionatto M, Pilapil M et al (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55(1):53–68. doi:10.1016/j.neuron.2007.05.030
Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ (2002) Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol 4(8):621–625. doi:10.1038/ncb833
Kuruvilla R, Ye H, Ginty DD (2000) Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 27(3):499–512
Zhou Y, Lu TJ, Xiong ZQ (2009) NGF-dependent retrograde signaling: survival versus death. Cell Res 19(5):525–526. doi:10.1038/cr.2009.47
Niewiadomska G, Mietelska-Porowska A, Mazurkiewicz M (2011) The cholinergic system, nerve growth factor and the cytoskeleton. Behav Brain Res 221(2):515–526. doi:10.1016/j.bbr.2010.02.024
Madziar B, Shah S, Brock M et al (2008) Nerve growth factor regulates the expression of the cholinergic locus and the high-affinity choline transporter via the Akt/PKB signaling pathway. J Neurochem 107(5):1284–1293. doi:10.1111/j.1471-4159.2008.05681.x
Markus A, Zhong J, Snider WD (2002) Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35(1):65–76
Deckwerth TL, Elliott JL, Knudson CM, Johnson EM Jr, Snider WD, Korsmeyer SJ (1996) BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17(3):401–411
Lentz SI, Knudson CM, Korsmeyer SJ, Snider WD (1999) Neurotrophins support the development of diverse sensory axon morphologies. J Neurosci 19(3):1038–1048
Liu RY, Snider WD (2001) Different signaling pathways mediate regenerative versus developmental sensory axon growth. J Neurosci 21(17):RC164
Namikawa K, Honma M, Abe K et al (2000) Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci 20(8):2875–2886
Culmsee C, Gerling N, Lehmann M, Nikolova-Karakashian M, Prehn JH, Mattson MP, Krieglstein J (2002) Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75. Neuroscience 115(4):1089–1108
Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR (1999) L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401(6754):703–708. doi:10.1038/44378
Kim MS, Shutov LP, Gnanasekaran A, Lin Z, Rysted JE, Ulrich JD, Usachev YM (2014) Nerve growth factor (NGF) regulates activity of nuclear factor of activated T-cells (NFAT) in neurons via the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3beta (GSK3beta) pathway. J Biol Chem 289(45):31349–31360. doi:10.1074/jbc.M114.587188
Bazenet CE, Mota MA, Rubin LL (1998) The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death. Proc Natl Acad Sci U S A 95(7):3984–3989
Rosario M, Franke R, Bednarski C, Birchmeier W (2007) The neurite outgrowth multiadaptor RhoGAP, NOMA-GAP, regulates neurite extension through SHP2 and Cdc42. J Cell Biol 178(3):503–516. doi:10.1083/jcb.200609146
Da Silva JS, Medina M, Zuliani C, Di Nardo A, Witke W, Dotti CG (2003) RhoA/ROCK regulation of neuritogenesis via profilin IIa-mediated control of actin stability. J Cell Biol 162(7):1267–1279. doi:10.1083/jcb.200304021
Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11(3):297–305. doi:10.1016/S0959-4388(00)00211-7
Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286(5443):1358–1362. doi:10.1126/science.286.5443.1358
Mullen LM, Pak KK, Chavez E, Kondo K, Brand Y, Ryan AF (2012) Ras/p38 and PI3K/Akt but not Mek/Erk signaling mediate BDNF-induced neurite formation on neonatal cochlear spiral ganglion explants. Brain Res 1430:25–34. doi:10.1016/j.brainres.2011.10.054
Kumar V, Zhang MX, Swank MW, Kunz J, Wu GY (2005) Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 25(49):11288–11299. doi:10.1523/JNEUROSCI.2284-05.2005
Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M (2005) Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci 25(49):11300–11312. doi:10.1523/JNEUROSCI.2270-05.2005
Nakazawa T, Tamai M, Mori N (2002) Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death through MAPK and PI3K signaling pathways. Invest Ophthalmol Vis Sci 43(10):3319–3326
Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000) Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20(7):2567–2574
Miller JR, Moon RT (1996) Signal transduction through beta-catenin and specification of cell fate during embryogenesis. Genes Dev 10(20):2527–2539
Hetman M, Hsuan SL, Habas A, Higgins MJ, Xia Z (2002) ERK1/2 antagonizes glycogen synthase kinase-3beta-induced apoptosis in cortical neurons. J Biol Chem 277(51):49577–49584. doi:10.1074/jbc.M111227200
Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 274(32):22569–22580. doi:10.1074/jbc.274.32.22569
Cohen P, Goedert M (2004) GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov 3(6):479–487. doi:10.1038/nrd1415
Davies AM, Horton A, Burton LE, Schmelzer C, Vandlen R, Rosenthal A (1993) Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. J Neurosci 13(11):4961–4967
Minichiello L, Casagranda F, Tatche RS, Stucky CL, Postigo A, Lewin GR, Davies AM, Klein R (1998) Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. Neuron 21(2):335–345
Vadodaria KC, Brakebusch C, Suter U, Jessberger S (2013) Stage-specific functions of the small Rho GTPases Cdc42 and Rac1 for adult hippocampal neurogenesis. J Neurosci 33(3):1179–1189. doi:10.1523/JNEUROSCI.2103-12.2013
Luikart BW, Zhang W, Wayman GA, Kwon CH, Westbrook GL, Parada LF (2008) Neurotrophin-dependent dendritic filopodial motility: a convergence on PI3K signaling. J Neurosci 28(27):7006–7012. doi:10.1523/JNEUROSCI.0195-08.2008
Liot G, Gabriel C, Cacquevel M, Ali C, MacKenzie ET, Buisson A, Vivien D (2004) Neurotrophin-3-induced PI-3 kinase/Akt signaling rescues cortical neurons from apoptosis. Exp Neurol 187(1):38–46. doi:10.1016/j.expneurol.2004.01.002
Kobayashi M, Matsuoka I (2000) Enhancement of sympathetic neuron survival by synergistic action of NT3 and GDNF. Neuroreport 11(11):2541–2545
Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3(5):383–394. doi:10.1038/nrn812
Funahashi Y, Namba T, Nakamuta S, Kaibuchi K (2014) Neuronal polarization in vivo: Growing in a complex environment. Curr Opin Neurobiol 27:215–223. doi:10.1016/j.conb.2014.04.009
Okada N, Wada K, Goldsmith BA, Koizumi S (1996) SHP-2 is involved in neurotrophin signaling. Biochem Biophys Res Commun 229(2):607–611. doi:10.1006/bbrc.1996.1851
Easton JB, Royer AR, Middlemas DS (2006) The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. J Neurochem 97(3):834–845. doi:10.1111/j.1471-4159.2006.03789.x
Goldsmith BA, Koizumi S (1997) Transient association of the phosphotyrosine phosphatase SHP-2 with TrkA is induced by nerve growth factor. J Neurochem 69(3):1014–1019
Dance M, Montagner A, Salles JP, Yart A, Raynal P (2008) The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal 20(3):453–459. doi:10.1016/j.cellsig.2007.10.002
Uren RT, Turnley AM (2014) Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player. Front Mol Neurosci 7:39. doi:10.3389/fnmol.2014.00039
Arevalo JC, Yano H, Teng KK, Chao MV (2004) A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J 23(12):2358–2368. doi:10.1038/sj.emboj.7600253
Feng GS (2007) Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res 17(1):37–41. doi:10.1038/sj.cr.7310140
Shen Y, Inoue N, Heese K (2010) Neurotrophin-4 (ntf4) mediates neurogenesis in mouse embryonic neural stem cells through the inhibition of the signal transducer and activator of transcription-3 (stat3) and the modulation of the activity of protein kinase B. Cell Mol Neurobiol 30(6):909–916. doi:10.1007/s10571-010-9520-1
Miranda C, Fumagalli T, Anania MC, Vizioli MG, Pagliardini S, Pierotti MA, Greco A (2010) Role of STAT3 in in vitro transformation triggered by TRK oncogenes. PLoS One 5(3), e9446. doi:10.1371/journal.pone.0009446
Yamauchi J, Miyamoto Y, Tanoue A, Shooter EM, Chan JR (2005) Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration. Proc Natl Acad Sci U S A 102(41):14889–14894. doi:10.1073/pnas.0507125102
Yamauchi J, Chan JR, Miyamoto Y, Tsujimoto G, Shooter EM (2005) The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration. Proc Natl Acad Sci U S A 102(14):5198–5203. doi:10.1073/pnas.0501160102
Cherfils J (2014) GEFs and GAPs: mechanisms and structures. In: Ras superfamily small G proteins: biology and mechanisms 1. Springer, pp 51–63
Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93(1):269–309. doi:10.1152/physrev.00003.2012
Yamauchi J, Chan JR, Shooter EM (2003) Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway. Proc Natl Acad Sci U S A 100(24):14421–14426. doi:10.1073/pnas.2336152100
Newbern JM, Li X, Shoemaker SE et al (2011) Specific functions for ERK/MAPK signaling during PNS development. Neuron 69(1):91–105. doi:10.1016/j.neuron.2010.12.003
Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA (2001) Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci 4(10):981–988. doi:10.1038/nn720
Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C (2009) Regulation of neuronal survival by the extracellular signal-regulated protein kinase 5. Cell Death Differ 16(5):674–683. doi:10.1038/cdd.2008.193
Morooka T, Nishida E (1998) Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem 273(38):24285–24288
Vaudry D, Stork PJ, Lazarovici P, Eiden LE (2002) Signaling pathways for PC12 cell differentiation: making the right connections. Science 296(5573):1648–1649. doi:10.1126/science.1071552
Li Y, Holtzman DM, Kromer LF, Kaplan DR, Chua-Couzens J, Clary DO, Knusel B, Mobley WC (1995) Regulation of TrkA and ChAT expression in developing rat basal forebrain: evidence that both exogenous and endogenous NGF regulate differentiation of cholinergic neurons. J Neurosci 15(4):2888–2905
Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6(8):603–614. doi:10.1038/nrn1726
Nagappan G, Lu B (2005) Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 28(9):464–471. doi:10.1016/j.tins.2005.07.003
Ortega JA, Alcantara S (2010) BDNF/MAPK/ERK-induced BMP7 expression in the developing cerebral cortex induces premature radial glia differentiation and impairs neuronal migration. Cereb Cortex 20(9):2132–2144. doi:10.1093/cercor/bhp275
Cheng A, Coksaygan T, Tang H, Khatri R, Balice-Gordon RJ, Rao MS, Mattson MP (2007) Truncated tyrosine kinase B brain-derived neurotrophic factor receptor directs cortical neural stem cells to a glial cell fate by a novel signaling mechanism. J Neurochem 100(6):1515–1530. doi:10.1111/j.1471-4159.2006.04337.x
Alonso M, Medina JH, Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11(2):172–178. doi:10.1101/lm.67804
Gottschalk WA, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B (1999) Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn Mem 6(3):243–256
Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, Lu B (2010) Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66(2):198–204. doi:10.1016/j.neuron.2010.03.035
Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76(2):99–125. doi:10.1016/j.pneurobio.2005.06.003
Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, Xia Z (2001) Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci 21(2):434–443
Wang W, Pan YW, Zou J, Li T, Abel GM, Palmiter RD, Storm DR, Xia Z (2014) Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory. J Neurosci 34(6):2130–2147. doi:10.1523/JNEUROSCI.3324-13.2014
Ohtsuka M, Fukumitsu H, Furukawa S (2009) Neurotrophin-3 stimulates neurogenetic proliferation via the extracellular signal-regulated kinase pathway. J Neurosci Res 87(2):301–306. doi:10.1002/jnr.21855
Aletsee C, Beros A, Mullen L, Palacios S, Pak K, Dazert S, Ryan AF (2001) Ras/MEK but not p38 signaling mediates NT-3-induced neurite extension from spiral ganglion neurons. J Assoc Res Otolaryngol 2(4):377–387
Ming G, Song H, Berninger B, Inagaki N, Tessier-Lavigne M, Poo M (1999) Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron 23(1):139–148
Yamashita T, Higuchi H, Tohyama M (2002) The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157(4):565–570. doi:10.1083/jcb.200202010
Yamashita T, Tohyama M (2003) The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat Neurosci 6(5):461–467. doi:10.1038/nn1045
Fujita Y, Yamashita T (2014) Axon growth inhibition by RhoA/ROCK in the central nervous system. Front Neurosci 8:338. doi:10.3389/fnins.2014.00338
Yamada M, Numakawa T, Koshimizu H, Tanabe K, Wada K, Koizumi S, Hatanaka H (2002) Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins. Brain Res 955(1-2):183–190
Numakawa T, Kumamaru E, Adachi N, Yagasaki Y, Izumi A, Kunugi H (2009) Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter. Proc Natl Acad Sci U S A 106(2):647–652. doi:10.1073/pnas.0800888106
Blanquet PR (2000) Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. Neuroscience 95(3):705–719
Blum R, Konnerth A (2005) Neurotrophin-mediated rapid signaling in the central nervous system: mechanisms and functions. Physiology (Bethesda) 20:70–78. doi:10.1152/physiol.00042.2004
Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M (2002) Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36(1):121–137
Mizoguchi Y, Ishibashi H, Nabekura J (2003) The action of BDNF on GABA(A) currents changes from potentiating to suppressing during maturation of rat hippocampal CA1 pyramidal neurons. J Physiol 548(Pt 3):703–709. doi:10.1113/jphysiol.2003.038935
Canossa M, Gartner A, Campana G, Inagaki N, Thoenen H (2001) Regulated secretion of neurotrophins by metabotropic glutamate group I (mGluRI) and Trk receptor activation is mediated via phospholipase C signalling pathways. EMBO J 20(7):1640–1650. doi:10.1093/emboj/20.7.1640
Yang F, He X, Feng L, Mizuno K, Liu XW, Russell J, Xiong WC, Lu B (2001) PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nat Neurosci 4(1):19–28. doi:10.1038/82858
Lee FS, Chao MV (2001) Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc Natl Acad Sci U S A 98(6):3555–3560. doi:10.1073/pnas.061020198
Lee FS, Rajagopal R, Chao MV (2002) Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev 13(1):11–17
Domeniconi M, Chao MV (2010) Transactivation of Trk receptors in spinal motor neurons. Histol Histopathol 25(9):1207–1213
Rajagopal R, Chen ZY, Lee FS, Chao MV (2004) Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J Neurosci 24(30):6650–6658. doi:10.1523/JNEUROSCI.0010-04.2004
Jeanneteau F, Chao MV (2006) Promoting neurotrophic effects by GPCR ligands. Novartis Found Symp 276:181–189, discussion 189–192, 233–187, 275–181
Lee FS, Rajagopal R, Kim AH, Chang PC, Chao MV (2002) Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J Biol Chem 277(11):9096–9102. doi:10.1074/jbc.M107421200
Wiese S, Jablonka S, Holtmann B, Orel N, Rajagopal R, Chao MV, Sendtner M (2007) Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB. Proc Natl Acad Sci U S A 104(43):17210–17215. doi:10.1073/pnas.0705267104
Puehringer D, Orel N, Luningschror P, Subramanian N, Herrmann T, Chao MV, Sendtner M (2013) EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons. Nat Neurosci 16(4):407–415. doi:10.1038/nn.3333
Fenner BM (2012) Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev 23(1-2):15–24. doi:10.1016/j.cytogfr.2012.01.002
Li YX, Xu Y, Ju D, Lester HA, Davidson N, Schuman EM (1998) Expression of a dominant negative TrkB receptor, T1, reveals a requirement for presynaptic signaling in BDNF-induced synaptic potentiation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 95(18):10884–10889
Steinbeck JA, Methner A (2005) Translational downregulation of the noncatalytic growth factor receptor TrkB.T1 by ischemic preconditioning of primary neurons. Gene Expr 12(2):99–106
Hartmann M, Brigadski T, Erdmann KS, Holtmann B, Sendtner M, Narz F, Lessmann V (2004) Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor. J Cell Sci 117(Pt 24):5803–5814. doi:10.1242/jcs.01511
Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16(10):3123–3129
Yacoubian TA, Lo DC (2000) Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci 3(4):342–349. doi:10.1038/73911
Brodeur GM, Minturn JE, Ho R et al (2009) Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15(10):3244–3250. doi:10.1158/1078-0432.CCR-08-1815
Carim-Todd L, Bath KG, Fulgenzi G et al (2009) Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo. J Neurosci 29(3):678–685. doi:10.1523/JNEUROSCI.5060-08.2009
Ohira K, Funatsu N, Homma KJ, Sahara Y, Hayashi M, Kaneko T, Nakamura S (2007) Truncated TrkB-T1 regulates the morphology of neocortical layer I astrocytes in adult rat brain slices. Eur J Neurosci 25(2):406–416. doi:10.1111/j.1460-9568.2007.05282.x
Ohira K, Kumanogoh H, Sahara Y, Homma KJ, Hirai H, Nakamura S, Hayashi M (2005) A truncated tropomyosin-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1. J Neurosci 25(6):1343–1353. doi:10.1523/JNEUROSCI.4436-04.2005
Ohira K, Homma KJ, Hirai H, Nakamura S, Hayashi M (2006) TrkB-T1 regulates the RhoA signaling and actin cytoskeleton in glioma cells. Biochem Biophys Res Commun 342(3):867–874. doi:10.1016/j.bbrc.2006.02.033
Fournier AE, Takizawa BT, Strittmatter SM (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci 23(4):1416–1423
Kozma R, Sarner S, Ahmed S, Lim L (1997) Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol Cell Biol 17(3):1201–1211
Aroeira RI, Sebastiao AM, Valente CA (2015) BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes. Glia 63(12):2181–2197. doi:10.1002/glia.22884
Michaelsen K, Zagrebelsky M, Berndt-Huch J, Polack M, Buschler A, Sendtner M, Korte M (2010) Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons. Eur J Neurosci 32(11):1854–1865. doi:10.1111/j.1460-9568.2010.07460.x
Kryl D, Barker PA (2000) TTIP is a novel protein that interacts with the truncated T1 TrkB neurotrophin receptor. Biochem Biophys Res Commun 279(3):925–930. doi:10.1006/bbrc.2000.4058
Palko ME, Coppola V, Tessarollo L (1999) Evidence for a role of truncated trkC receptor isoforms in mouse development. J Neurosci 19(2):775–782
Menn B, Timsit S, Calothy G, Lamballe F (1998) Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association. J Comp Neurol 401(1):47–64
Esteban PF, Yoon HY, Becker J et al (2006) A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin. J Cell Biol 173(2):291–299. doi:10.1083/jcb.200512013
Ibanez CF, Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35(7):431–440. doi:10.1016/j.tins.2012.03.007
Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350(6320):678–683. doi:10.1038/350678a0
Esposito D, Patel P, Stephens RM, Perez P, Chao MV, Kaplan DR, Hempstead BL (2001) The cytoplasmic and transmembrane domains of the p75 and Trk A receptors regulate high affinity binding to nerve growth factor. J Biol Chem 276(35):32687–32695. doi:10.1074/jbc.M011674200
Meeker R, Williams K (2014) Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol 9(5):615–628. doi:10.1007/s11481-014-9566-9
Gentry JJ, Rutkoski NJ, Burke TL, Carter BD (2004) A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF. J Biol Chem 279(16):16646–16656. doi:10.1074/jbc.M309209200
Linggi MS, Burke TL, Williams BB, Harrington A, Kraemer R, Hempstead BL, Yoon SO, Carter BD (2005) Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor. J Biol Chem 280(14):13801–13808. doi:10.1074/jbc.M410435200
Salehi AH, Xanthoudakis S, Barker PA (2002) NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway. J Biol Chem 277(50):48043–48050. doi:10.1074/jbc.M205324200
Westwick JK, Bielawska AE, Dbaibo G, Hannun YA, Brenner DA (1995) Ceramide activates the stress-activated protein kinases. J Biol Chem 270(39):22689–22692
Brann AB, Tcherpakov M, Williams IM, Futerman AH, Fainzilber M (2002) Nerve growth factor-induced p75-mediated death of cultured hippocampal neurons is age-dependent and transduced through ceramide generated by neutral sphingomyelinase. J Biol Chem 277(12):9812–9818. doi:10.1074/jbc.M109862200
Hamanoue M, Middleton G, Wyatt S, Jaffray E, Hay RT, Davies AM (1999) p75-mediated NF-kappaB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol Cell Neurosci 14(1):28–40. doi:10.1006/mcne.1999.0770
Khursigara G, Orlinick JR, Chao MV (1999) Association of the p75 neurotrophin receptor with TRAF6. J Biol Chem 274(5):2597–2600
Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R, Baeuerle PA, Barde YA (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272(5261):542–545
Khursigara G, Bertin J, Yano H, Moffett H, DiStefano PS, Chao MV (2001) A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. J Neurosci 21(16):5854–5863
Lebrun-Julien F, Bertrand MJ, De Backer O, Stellwagen D, Morales CR, Di Polo A, Barker PA (2010) ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. Proc Natl Acad Sci U S A 107(8):3817–3822. doi:10.1073/pnas.0909276107
Volosin M, Trotter C, Cragnolini A, Kenchappa RS, Light M, Hempstead BL, Carter BD, Friedman WJ (2008) Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures. J Neurosci 28(39):9870–9879. doi:10.1523/JNEUROSCI.2841-08.2008
Kenchappa RS, Zampieri N, Chao MV, Barker PA, Teng HK, Hempstead BL, Carter BD (2006) Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons. Neuron 50(2):219–232. doi:10.1016/j.neuron.2006.03.011
Geetha T, Kenchappa RS, Wooten MW, Carter BD (2005) TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor. EMBO J 24(22):3859–3868. doi:10.1038/sj.emboj.7600845
Chen J, Wu X, Shao B, Zhao W, Shi W, Zhang S, Ni L, Shen A (2011) Increased expression of TNF receptor-associated factor 6 after rat traumatic brain injury. Cell Mol Neurobiol 31(2):269–275. doi:10.1007/s10571-010-9617-6
Wu X, Xu XM (2016) RhoA/Rho kinase in spinal cord injury. Neural Regen Res 11(1):23–27. doi:10.4103/1673-5374.169601
Meeker RB, Williams KS (2015) The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen Res 10(5):721–725. doi:10.4103/1673-5374.156967
Yamashita T, Tucker KL, Barde YA (1999) Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24(3):585–593. doi:10.1016/S0896-6273(00)81114-9
Song W, Volosin M, Cragnolini AB, Hempstead BL, Friedman WJ (2010) ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J Neurosci 30(46):15608–15615. doi:10.1523/JNEUROSCI.2581-10.2010
Sheng M, Sabatini BL, Sudhof TC (2012) Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol 4(5). doi:10.1101/cshperspect.a005777
Picconi B, Piccoli G, Calabresi P (2012) Synaptic dysfunction in Parkinson’s disease. Adv Exp Med Biol 970:553–572. doi:10.1007/978-3-7091-0932-8_24
Sudhof TC, Rizo J (2011) Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol 3(12). doi:10.1101/cshperspect.a005637
Calabresi P, Mercuri NB, Di Filippo M (2009) Synaptic plasticity, dopamine and Parkinson’s disease: one step ahead. Brain 132(Pt 2):285–287. doi:10.1093/brain/awn340
Tancredi V, D’Arcangelo G, Mercanti D, Calissano P (1993) Nerve growth factor inhibits the expression of long-term potentiation in hippocampal slices. Neuroreport 4(2):147–150
Brancucci A, Kuczewski N, Covaceuszach S, Cattaneo A, Domenici L (2004) Nerve growth factor favours long-term depression over long-term potentiation in layer II-III neurones of rat visual cortex. J Physiol 559(Pt 2):497–506. doi:10.1113/jphysiol.2004.068049
Akaneya Y, Tsumoto T, Kinoshita S, Hatanaka H (1997) Brain-derived neurotrophic factor enhances long-term potentiation in rat visual cortex. J Neurosci 17(17):6707–6716
Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR, Sejnowski TJ, Tuszynski MH (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29(35):10883–10889. doi:10.1523/JNEUROSCI.2594-09.2009
Arias ER, Valle-Leija P, Morales MA, Cifuentes F (2014) Differential contribution of BDNF and NGF to long-term potentiation in the superior cervical ganglion of the rat. Neuropharmacology 81:206–214. doi:10.1016/j.neuropharm.2014.02.001
Edelmann E, Lessmann V, Brigadski T (2014) Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76(Pt C):610–627. doi:10.1016/j.neuropharm.2013.05.043
Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–250. doi:10.1007/978-3-642-45106-5_9
Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M (1992) Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9(6):1081–1088
Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381(6584):706–709. doi:10.1038/381706a0
Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92(19):8856–8860
Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16(6):1137–1145
Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8(8):1069–1077. doi:10.1038/nn1510
Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde YA (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11(2):131–133. doi:10.1038/nn2038
Bliss TV, Cooke SF (2011) Long-term potentiation and long-term depression: a clinical perspective. Clinics (Sao Paulo) 66(Suppl 1):3–17
Bliss TV, Collingridge GL, Morris RG (2014) Synaptic plasticity in health and disease: introduction and overview. Philos Trans R Soc Lond B Biol Sci 369 (1633):20130129. doi:10.1098/rstb.2013.0129
Chen G, Kolbeck R, Barde YA, Bonhoeffer T, Kossel A (1999) Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation. J Neurosci 19(18):7983–7990
Ma L, Reis G, Parada LF, Schuman EM (1999) Neuronal NT-3 is not required for synaptic transmission or long-term potentiation in area CA1 of the adult rat hippocampus. Learn Mem 6(3):267–275
Kaplan DR, Cooper E (2001) PI-3 kinase and IP3: partners in NT3-induced synaptic transmission. Nat Neurosci 4(1):5–7. doi:10.1038/82897
Galvan EJ, Cosgrove KE, Barrionuevo G (2011) Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses on interneurons. Neuropharmacology 60(5):740–747. doi:10.1016/j.neuropharm.2010.11.008
Ramos-Languren LE, Escobar ML (2013) Plasticity and metaplasticity of adult rat hippocampal mossy fibers induced by neurotrophin-3. Eur J Neurosci 37(8):1248–1259. doi:10.1111/ejn.12141
Xie CW, Sayah D, Chen QS, Wei WZ, Smith D, Liu X (2000) Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene. Proc Natl Acad Sci U S A 97(14):8116–8121. doi:10.1073/pnas.140204597
Fan G, Egles C, Sun Y, Minichiello L, Renger JJ, Klein R, Liu G, Jaenisch R (2000) Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat Neurosci 3(4):350–357. doi:10.1038/73921
Zeng Y, Zhao D, Xie CW (2010) Neurotrophins enhance CaMKII activity and rescue amyloid-beta-induced deficits in hippocampal synaptic plasticity. J Alzheimers Dis 21(3):823–831. doi:10.3233/JAD-2010-100264
Callaghan CK, Kelly AM (2013) Neurotrophins play differential roles in short and long-term recognition memory. Neurobiol Learn Mem 104:39–48. doi:10.1016/j.nlm.2013.04.011
Wondolowski J, Dickman D (2013) Emerging links between homeostatic synaptic plasticity and neurological disease. Front Cell Neurosci 7:223. doi:10.3389/fncel.2013.00223
Stewart MH, Bendall SC, Bhatia M (2008) Deconstructing human embryonic stem cell cultures: niche regulation of self-renewal and pluripotency. J Mol Med (Berl) 86(8):875–886. doi:10.1007/s00109-008-0356-9
Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA (2000) Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 227(2):271–278. doi:10.1006/dbio.2000.9912
Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N (2000) Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 97(21):11307–11312. doi:10.1073/pnas.97.21.11307
Bentz K, Molcanyi M, Riess P et al (2007) Embryonic stem cells produce neurotrophins in response to cerebral tissue extract: Cell line-dependent differences. J Neurosci Res 85(5):1057–1064. doi:10.1002/jnr.21219
Moscatelli I, Pierantozzi E, Camaioni A, Siracusa G, Campagnolo L (2009) p75 neurotrophin receptor is involved in proliferation of undifferentiated mouse embryonic stem cells. Exp Cell Res 315(18):3220–3232. doi:10.1016/j.yexcr.2009.08.014
Wobus AM, Grosse R, Schoneich J (1988) Specific effects of nerve growth factor on the differentiation pattern of mouse embryonic stem cells in vitro. Biomed Biochim Acta 47(12):965–973
Schuldiner M, Eiges R, Eden A, Yanuka O, Itskovitz-Eldor J, Goldstein RS, Benvenisty N (2001) Induced neuronal differentiation of human embryonic stem cells. Brain Res 913(2):201–205. doi:10.1016/S0006-8993(01)02776-7
Levenberg S, Burdick JA, Kraehenbuehl T, Langer R (2005) Neurotrophin-induced differentiation of human embryonic stem cells on three-dimensional polymeric scaffolds. Tissue Eng 11(3-4):506–512. doi:10.1089/ten.2005.11.506
Leschik J, Eckenstaler R, Nieweg K, Lichtenecker P, Brigadski T, Gottmann K, Lessmann V, Lutz B (2013) Embryonic stem cells stably expressing BDNF-GFP exhibit a BDNF-release-dependent enhancement of neuronal differentiation. J Cell Sci 126(Pt 21):5062–5073. doi:10.1242/jcs.135384
Xu R, Srinivasan SP, Sureshkumar P et al (2015) Effects of synthetic neural adhesion molecule mimetic peptides and related proteins on the cardiomyogenic differentiation of mouse embryonic stem cells. Cell Physiol Biochem 35(6):2437–2450. doi:10.1159/000374044
Gage FH, Temple S (2013) Neural stem cells: generating and regenerating the brain. Neuron 80(3):588–601. doi:10.1016/j.neuron.2013.10.037
Lindvall O, Kokaia Z (2011) Stem cell research in stroke: how far from the clinic? Stroke 42(8):2369–2375. doi:10.1161/STROKEAHA.110.599654
Tong LM, Fong H, Huang Y (2015) Stem cell therapy for Alzheimer’s disease and related disorders: current status and future perspectives. Exp Mol Med 47, e151. doi:10.1038/emm.2014.124
Islam O, Loo TX, Heese K (2009) Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Curr Neurovasc Res 6(1):42–53. doi:10.2174/156720209787466028#sthash.4DDR9O4h.dpuf
Lachyankar MB, Condon PJ, Quesenberry PJ, Litofsky NS, Recht LD, Ross AH (1997) Embryonic precursor cells that express Trk receptors: induction of different cell fates by NGF, BDNF, NT-3, and CNTF. Exp Neurol 144(2):350–360. doi:10.1006/exnr.1997.6434
Ahmed S, Reynolds B, Weiss S (1995) BDNF enhances the differentiation but not the survival of CNS stem cell- derived neuronal precursors. J Neurosci 15(8):5765–5778
Yan Q, Radeke MJ, Matheson CR, Talvenheimo J, Welcher AA, Feinstein SC (1997) Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J Comp Neurol 378(1):135–157. doi:10.1002/(SICI)1096-9861(19970203)378:1<135::AID-CNE8>3.0.CO;2-5
Fong SP, Tsang KS, Chan AB, Lu G, Poon WS, Li K, Baum LW, Ng HK (2007) Trophism of neural progenitor cells to embryonic stem cells: neural induction and transplantation in a mouse ischemic stroke model. J Neurosci Res 85(9):1851–1862. doi:10.1002/jnr.21319
Takahashi J, Palmer TD, Gage FH (1999) Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J Neurobiol 38(1):65–81. doi:10.1002/(SICI)1097-4695(199901)38:1<65::AID-NEU5>3.0.CO;2-Q
Barnabe-Heider F, Miller FD (2003) Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci 23(12):5149–5160
Temple S, Qian X (1995) bFGF, neurotrophins, and the control or cortical neurogenesis. Neuron 15(2):249–252. doi:10.1016/0896-6273(95)90030-6
Caldwell MA, He X, Wilkie N, Pollack S, Marshall G, Wafford KA, Svendsen CN (2001) Growth factors regulate the survival and fate of cells derived from human neurospheres. Nat Biotechnol 19(5):475–479. doi:10.1038/88158
Liu F, Xuan A, Chen Y, Zhang J, Xu L, Yan Q, Long D (2014) Combined effect of nerve growth factor and brainderived neurotrophic factor on neuronal differentiation of neural stem cells and the potential molecular mechanisms. Mol Med Rep 10(4):1739–1745. doi:10.3892/mmr.2014.2393
Ito H, Nakajima A, Nomoto H, Furukawa S (2003) Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix-loop-helix transcription factors Mash1 and Math1. J Neurosci Res 71(5):648–658. doi:10.1002/jnr.10532
Chen BY, Wang X, Wang ZY, Wang YZ, Chen LW, Luo ZJ (2013) Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/beta-catenin signaling pathway. J Neurosci Res 91(1):30–41. doi:10.1002/jnr.23138
Tervonen TA, Ajamian F, De Wit J, Verhaagen J, Castren E, Castren M (2006) Overexpression of a truncated TrkB isoform increases the proliferation of neural progenitors. Eur J Neurosci 24(5):1277–1285. doi:10.1111/j.1460-9568.2006.05010.x
Chen SQ, Cai Q, Shen YY, Cai XY, Lei HY (2014) Combined use of NGF/BDNF/bFGF promotes proliferation and differentiation of neural stem cells in vitro. Int J Dev Neurosci 38:74–78. doi:10.1016/j.ijdevneu.2014.08.002
Lu HX, Hao ZM, Jiao Q et al (2011) Neurotrophin-3 gene transduction of mouse neural stem cells promotes proliferation and neuronal differentiation in organotypic hippocampal slice cultures. Med Sci Monit 17(11):BR305–BR311. doi:10.12659/MSM.882039
Jin L, Hu X, Feng L (2005) NT3 inhibits FGF2-induced neural progenitor cell proliferation via the PI3K/GSK3 pathway. J Neurochem 93(5):1251–1261. doi:10.1111/j.1471-4159.2005.03118.x
Jansson LC, Louhivuori L, Wigren HK, Nordstrom T, Louhivuori V, Castren ML, Akerman KE (2012) Brain-derived neurotrophic factor increases the motility of a particular N-methyl-D-aspartate/GABA-responsive subset of neural progenitor cells. Neuroscience 224:223–234. doi:10.1016/j.neuroscience.2012.08.038
Grade S, Weng YC, Snapyan M, Kriz J, Malva JO, Saghatelyan A (2013) Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum. PLoS One 8(1), e55039. doi:10.1371/journal.pone.0055039
Zhang Q, Liu G, Wu Y, Sha H, Zhang P, Jia J (2011) BDNF promotes EGF-induced proliferation and migration of human fetal neural stem/progenitor cells via the PI3K/Akt pathway. Molecules 16(12):10146–10156. doi:10.3390/molecules161210146
Behar TN, Dugich-Djordjevic MM, Li YX et al (1997) Neurotrophins stimulate chemotaxis of embryonic cortical neurons. Eur J Neurosci 9(12):2561–2570. doi:10.1111/j.1460-9568.1997.tb01685.x
Delgado AC, Ferron SR, Vicente D, Porlan E, Perez-Villalba A, Trujillo CM, D’Ocon P, Farinas I (2014) Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. Neuron 83(3):572–585. doi:10.1016/j.neuron.2014.06.015
Lindvall O, Ernfors P, Bengzon J, Kokaia Z, Smith ML, Siesjo BK, Persson