Abstract
Neurogenesis occurs in two regions of the adult brain, namely, the subventricular zone (SVZ) throughout the wall of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) in hippocampal formation. Adult neurogenesis requires several neurotrophic factors to sustain and regulate the proliferation and differentiation of the adult stem cell population. In the present review, we examine the cellular and functional aspects of a trophic system mediated by fibroblast growth factor-2 (FGF-2) and its receptors (FGFRs) related to neurogenesis in the SVZ and SGZ of the adult rat brain. In the SVZ, FGF-2 is expressed in GFAP-positive cells of SVZ but is not present in proliferating precursor cells, which instead express FGFR-1 and FGFR-2, but not FGFR-3 mRNA, although expressed in the SVZ, and FGFR-4. Therefore, it seems that in the SVZ FGF-2 may be released by GFAP-positive cells, different from the precursor cell lineage, and via volume transmission it reaches the proliferating precursor cells. FGFR-1 mRNA is also expressed in the SGZ and is localized in BrdU-labeled precursor cells, whereas FGFR-2 and FGFR-3 mRNA, although expressed in the SGZ, are not located within proliferating precursor cells. An aged-related decline of proliferating precursor cells in the SVZ and DG of old rats has been well documented, and there is the suggestion that in part it could be the consequence of alterations in growth factor expression levels. Thus, the old precursors may respond to growth factors, suggesting that during aging the basic components for neuronal precursor cell proliferation are retained and the capacity to increase neurogenesis after appropriate stimulation is still preserved. In conclusion, the trophic system mediated by FGF-2 and its receptors contributes to create an important micro-environmental niche that promotes neurogenesis in the adult and aged brain.
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References
Abrous DN, Adriani W, Montaron MF, Aurousseau C, Rougon G, Le MM, Piazza PV (2002) Nicotine self-administration impairs hippocampal plasticity. J Neurosci 22:3656–3662
Abrous DN, Koehl M, Le MM (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569
Altman J (1962) Are new neurons formed in the brains of adult mammals? Science 135:1127–1128
Alvarez-Buylla A, Garcia-Verdugo JM (2002) Neurogenesis in adult subventricular zone. J Neurosci 22:629–634
Alvarez-Buylla A, Lim DA (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41:683–686
Alvarez-Buylla A, Seri B, Doetsch F (2002) Identification of neural stem cells in the adult vertebrate brain. Brain Res Bull 57:751–758
Atluri P, Fleck MW, Shen Q, Mah SJ, Stadfelt D, Barnes W, Goderie SK, Temple S, Schneider AS (2001) Functional nicotinic acetylcholine receptor expression in stem and progenitor cells of the early embryonic mouse cerebral cortex. Dev Biol 240:143–156
Belluardo N, Wu G, Mudo G, Hansson AC, Pettersson R, Fuxe K (1997) Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: in situ hybridization analysis. J Comp Neurol 379:226–246
Belluardo N, Mudo G, Blum M, Itoh N, Agnati L, Fuxe K (2004) Nicotine-induced FGF-2 mRNA in rat brain is preserved during aging. Neurobiol Aging 25:1333–1342
Belluardo N, Mudó G, Bonomo A, Di Liberto V, Frinchi M, Fuxe K (2008) Nicotine-induced fibroblast growth factor-2 restores the age-related decline of precursor cell proliferation in the subventricular zone of rat brain. Brain Res 1193:12–24
Bizon JL, Gallagher M (2003) Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline. Eur J NeuroSci 18:215–219
Bonfanti L, Theodosis DT (1994) Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb. Neuroscience 62:291–305
Bull ND, Bartlett PF (2005) The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J Neurosci 25:10815–10821
Cameron HA, McKay RD (1999) Restoring production of hippocampal neurons in old age. Nat Neurosci 2:894–897
Cameron HA, Hazel TG, McKay RD (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36:287–306
Carlen M, Cassidy RM, Brismar H, Smith GA, Enquist LW, Frisen J (2002) Functional integration of adult-born neurons. Curr Biol 12:606–608
Carleton A, Petreanu LT, Lansford R, varez-Buylla A, Lledo PM (2003) Becoming a new neuron in the adult olfactory bulb. Nat Neurosci 6:507–518
Chadashvili T, Peterson DA (2006) Cytoarchitecture of fibroblast growth factor receptor 2 (FGFR-2) immunoreactivity in astrocytes of neurogenic and non-neurogenic regions of the young adult and aged rat brain. J Comp Neurol 498:1–15
Cheng Y, Black IB, Cicco-Bloom E (2002) Hippocampal granule neuron production and population size are regulated by levels of bFGF. Eur J NeuroSci 15:3–12
Chiasson BJ, Tropepe V, Morshead CM, van der Kooy D (1999) Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci 19:4462–4471
Clarke DJ, Dunnett SB (1993) Synaptic relationships between cortical and dopaminergic inputs and intrinsic GABAergic systems within intrastriatal striatal grafts. J Chem Neuroanat 6:147–158
Conover JC, Notti RQ (2008) The neural stem cell niche. Cell Tissue Res 331:211–224
Cooper-Kuhn CM, Winkler J, Kuhn HG (2004) Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res 77:155–165
Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der Kooy D (1996) In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 16:2649–2658
Doetsch F, Garcia-Verdugo JM, varez-Buylla A (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17:5046–5061
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716
Drapeau E, Mayo W, Aurousseau C, Le MM, Piazza PV, Abrous DN (2003) Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA 100:14385–14390
Dvorak P, Dvorakova D, Koskova S, Vodinska M, Najvirtova M, Krekac D, Hampl A (2005) Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells. Stem Cells 23(8):1200–1211
Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S (2004) Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24:8354–8365
Ernfors P, Lonnerberg P, yer-LeLievre C, Persson H (1990) Developmental and regional expression of basic fibroblast growth factor mRNA in the rat central nervous system. J Neurosci Res 27:10–15
Frinchi M, Bonomo A, Trovato-Salinaro A, Condorelli DF, Fuxe K, Spampinato MG, Mudo G (2008) Fibroblast growth factor-2 and its receptor expression in proliferating precursor cells of the subventricular zone in the adult rat brain. Neurosci Lett 447(1):20–25
Fuxe K, Tinner B, Zoli M, Pettersson RF, Baird A, Biagini G, Chadi G, Agnati LF (1996) Computer-assisted mapping of basic fibroblast growth factor immunoreactive nerve cell populations in the rat brain. J Chem Neuroanat 11:13–35
Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438
Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 18:159–192
Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray J (1998) Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol 36:249–266
Ganat Y, Soni S, Chacon M, Schwartz ML, Vaccarino FM (2002) Chronic hypoxia up-regulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor-responsive radial glial cells in the sub-ependymal zone. Neuroscience 112:977–991
Garcia-Verdugo JM, Doetsch F, Wichterle H, Lim DA, Alvarez-Buylla A (1998) Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol 36:234–248
Ghosh A, Greenberg ME (1995) Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis. Neuron 15:89–103
Goldman SA (1998) Adult neurogenesis: from canaries to the clinic. J Neurobiol 36:267–286
Gomez-Pinilla F, Dao L, So V (1997) Physical exercise induces FGF-2 and its mRNA in the hippocampus. Brain Res 764:1–8
Gonzalez AM, Carman LS, Ong M, Ray J, Gage FH, Shults CW, Baird A (1994) Storage, metabolism, and processing of 125I-fibroblast growth factor-2 after intracerebral injection. Brain Res 665:285–292
Gonzalez AM, Berry M, Maher PA, Logan A, Baird A (1995) A comprehensive analysis of the distribution of FGF-2 and FGFR1 in the rat brain. Brain Res 701:201–226
Gould E, Tanapat P (1999) Stress and hippocampal neurogenesis. Biol Psychiatry 46:1472–1479
Gould E, Reeves AJ, Graziano MS, Gross CG (1999) Neurogenesis in the neocortex of adult primates. Science 286:548–552
Gritti A, Parati EA, Cova L, Frolichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL (1996) Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci 16:1091–1100
Gritti A, Frolichsthal-Schoeller P, Galli R, Parati EA, Cova L, Pagano SF, Bjornson CR, Vescovi AL (1999) Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J Neurosci 19:3287–3297
Gros A, Wevers A, Hedayat F, Richter R, Birtsch C, Lindstrom JM, Schroder H (1999) Expression of nicotinic acetylcholine receptor subunits during development of the rat neocortex. SFN annual meeting in Miami Beach, Florida, 23–28, Oct. Soc Neurosci Abstr 25:#891.7
Hagg T (2005) Molecular regulation of adult CNS neurogenesis: an integrated view. Trends Neurosci 28:589–595
Hallbergson AF, Gnatenco C, Peterson DA (2003) Neurogenesis and brain injury: managing a renewable resource for repair. J Clin Invest 112:1128–1133
Harrist A, Beech RD, King SL, Zanardi A, Cleary MA, Caldarone BJ, Eisch A, Zoli M, Picciotto MR (2004) Alteration of hippocampal cell proliferation in mice lacking the beta 2 subunit of the neuronal nicotinic acetylcholine receptor. Synapse 54:200–206
Hastings NB, Gould E (1999) Rapid extension of axons into the CA3 region by adult-generated granule cells. J Comp Neurol 413:146–154
Hattiangady B, Shetty AK (2008) Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol Aging 29:129–147
Hattiangady B, Rao MS, Shetty GA, Shetty AK (2005) Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol 195:353–371
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950
Jin K, Sun Y, Xie L, Batteur S, Mao XO, Smelick C, Logvinova A, Greenberg DA (2003a) Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell 2:175–183
Jin K, Xie L, Childs J, Sun Y, Mao XO, Logvinova A, Greenberg DA (2003b) Cerebral neurogenesis is induced by intranasal administration of growth factors. Ann Neurol 53:405–409
Jin K, LaFevre-Bernt M, Sun Y, Chen S, Gafni J, Crippen D, Logvinova A, Ross CA, Greenberg DA, Ellerby LM (2005) FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 102:18189–18194
Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96:25–34
Kalyani A, Hobson K, Rao MS (1997) Neuroepithelial stem cells from the embryonic spinal cord: isolation, characterization, and clonal analysis. Dev Biol 186:202–223
Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362
Kempermann G, Kuhn HG, Gage FH (1998) Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18:3206–3212
Kilpatrick TJ, Bartlett PF (1993) Cloning and growth of multipotential neural precursors: requirements for proliferation and differentiation. Neuron 10:255–265
Kilpatrick TJ, Bartlett PF (1995) Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF. J Neurosci 15:3653–3661
Kosaka N, Kodama M, Sasaki H, Yamamoto Y, Takeshita F, Takahama Y, Sakamoto H, Kato T, Terada M, Ochiya T (2006) FGF-4 regulates neural progenitor cell proliferation and neuronal differentiation. FASEB J 20:1484–1485
Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033
Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH (1997) Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 17:5820–5829
Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR (2001) Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107:603–613
Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH (2002) The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 22:6639–6649
Lin TN, Te J, Lee M, Sun GY, Hsu CY (1997) Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia. Brain Res Mol Brain Res 49:255–265
Liu S, Wang J, Zhu D, Fu Y, Lukowiak K, Lu YM (2003) Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci 23:732–736
Luo J, Daniels SB, Lennington JB, Notti RQ, Conover JC (2006) The aging neurogenic subventricular zone. Aging Cell 5:139–152
Markakis EA, Gage FH (1999) Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol 406:449–460
Maslov AY, Barone TA, Plunkett RJ, Pruitt SC (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24:1726–1733
McKay R (1997) Stem cells in the central nervous system. Science 276:66–71
Miragall F, Kadmon G, Faissner A, Antonicek H, Schachner M (1990) Retention of J1/tenascin and the polysialylated form of the neural cell adhesion molecule (N-CAM) in the adult olfactory bulb. J Neurocytol 19:899–914
Mohapel P, Leanza G, Kokaia M, Lindvall O (2005) Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26:939–946
Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082
Morshead CM, Craig CG, van der Kooy D (1998) In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development 125:2251–2261
Mudo G, Belluardo N, Mauro A, Fuxe K (2007) Acute intermittent nicotine treatment induces fibroblast growth factor-2 in the subventricular zone of the adult rat brain and enhances neuronal precursor cell proliferation. Neuroscience 145:470–483
Murphy M, Drago J, Bartlett PF (1990) Fibroblast growth factor stimulates the proliferation and differentiation of neural precursor cells in vitro. J Neurosci Res 25:463–475
Nacher J, onso-Llosa G, Rosell DR, McEwen BS (2003) NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging 24:273–284
Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110:429–441
Newman MP, Feron F, kay-Sim A (2000) Growth factor regulation of neurogenesis in adult olfactory epithelium. Neuroscience 99:343–350
Ohkubo Y, Uchida AO, Shin D, Partanen J, Vaccarino FM (2004) Fibroblast growth factor receptor 1 is required for the proliferation of hippocampal progenitor cells and for hippocampal growth in mouse. J Neurosci 24:6057–6069
Okano HJ, Pfaff DW, Gibbs RB (1996) Expression of EGFR-, p75NGFR-, and PSTAIR (cdc2)-like immunoreactivity by proliferating cells in the adult rat hippocampal formation and forebrain. Dev Neurosci 18:199–209
Olariu A, Cleaver KM, Cameron HA (2007) Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle. J Comp Neurol 501:659–667
Ornitz DM (2000) FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays 22:108–112
Orr-Urtreger A, Givol D, Yayon A, Yarden Y, Lonai P (1991) Developmental expression of two murine fibroblast growth factor receptors, flg and bek. Development 113:1419–1434
Orr-Urtreger A, Broide RS, Kasten MR, Dang H, Dani JA, Beaudet AL, Patrick JW (2000) Mice homozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth. J Neurochem 74:2154–2166
Palmer TD, Ray J, Gage FH (1995) FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 6:474–486
Palmer TD, Takahashi J, Gage FH (1997) The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8:389–404
Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage FH (1999) Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 19:8487–8497
Peters K, Ornitz D, Werner S, Williams L (1993) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol 155:423–430
Petreanu L, Alvarez-Buylla A (2002) Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J Neurosci 22:6106–6113
Pieper AA, Wu X, Han TW, Estill SJ, Dang Q, Wu LC, Reece-Fincanon S, Dudley CA, Richardson JA, Brat DJ, McKnight SL (2005) The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc Natl Acad Sci USA 102:14052–14057
Quinn SM, Walters WM, Vescovi AL, Whittemore SR (1999) Lineage restriction of neuroepithelial precursor cells from fetal human spinal cord. J Neurosci Res 57:590–602
Raballo R, Rhee J, Lyn-Cook R, Leckman JF, Schwartz ML, Vaccarino FM (2000) Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex. J Neurosci 20:5012–5023
Rai KS, Hattiangady B, Shetty AK (2007) Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions. Eur J NeuroSci 26:1765–1779
Ramirez-Castillejo C, Sanchez-Sanchez F, Andreu-Agullo C, Ferron SR, roca-Aguilar JD, Sanchez P, Mira H, Escribano J, Farinas I (2006) Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci 9:331–339
Rao MS, Hattiangady B, Shetty AK (2006) The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 5:545–558
Ray J, Gage FH (1994) Spinal cord neuroblasts proliferate in response to basic fibroblast growth factor. J Neurosci 14:3548–3564
Ray J, Peterson DA, Schinstine M, Gage FH (1993) Proliferation, differentiation, and long-term culture of primary hippocampal neurons. Proc Natl Acad Sci USA 90:3602–3606
Reuss B, von Bohlen und Halbach O (2003) Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 313:139–157
Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2:149–168
Rossi FM, Pizzorusso T, Porciatti V, Marubio LM, Maffei L, Changeux JP (2001) Requirement of the nicotinic acetylcholine receptor beta 2 subunit for the anatomical and functional development of the visual system. Proc Natl Acad Sci USA 98:6453–6458
Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C, Fraser RA, Couldwell WT, Kawaguchi A, Okano H, Nedergaard M, Goldman SA (2000) In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6:271–277
Santa-Olalla J, Covarrubias L (1995) Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and basic fibroblast growth factor (bFGF) differentially influence neural precursor cells of mouse embryonic mesencephalon. J Neurosci Res 42:172–183
Sargent PB (1993) The diversity of neuronal nicotinic acetylcholine receptors. Annu Rev Neurosci 16:403–443
Seaberg RM, van der Kooy D (2002) Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci 22:1784–1793
Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, varez-Buylla A (2004) Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 478:359–378
Shetty AK, Hattiangady B, Shetty GA (2005) Stem/progenitor cell proliferation factors FGF-2, IGF-1, and VEGF exhibit early decline during the course of aging in the hippocampus: role of astrocytes. Glia 51:173–186
Song HJ, Stevens CF, Gage FH (2002) Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci 5:438–445
Stanfield BB, Trice JE (1988) Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res 72:399–406
Tao Y, Black IB, Cicco-Bloom E (1996) Neurogenesis in neonatal rat brain is regulated by peripheral injection of basic fibroblast growth factor (bFGF). J Comp Neurol 376:653–663
Tao Y, Black IB, Cicco-Bloom E (1997) In vivo neurogenesis is inhibited by neutralizing antibodies to basic fibroblast growth factor. J Neurobiol 33:289–296
Temple S, Alvarez-Buylla A (1999) Stem cells in the adult mammalian central nervous system. Curr Opin Neurobiol 9:135–141
Temple S, Qian X (1995) bFGF, neurotrophins, and the control or cortical neurogenesis. Neuron 15:249–252
Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman MH, Gage FH (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10:727–734
Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634
Tropepe V, Craig CG, Morshead CM, van der Kooy D (1997) Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci 17:7850–7859
Tropepe V, Sibilia M, Ciruna BG, Rossant J, Wagner EF, van der Kooy D (1999) Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev Biol 208:166–188
Vaccarino FM, Schwartz ML, Raballo R, Nilsen J, Rhee J, Zhou M, Doetschman T, Coffin JD, Wyland JJ, Hung YT (1999) Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis. Nat Neurosci 2:246–253
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96:13427–13431
van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191–198
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034
Vescovi AL, Reynolds BA, Fraser DD, Weiss S (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11:951–966
Vicario-Abejon C, Johe KK, Hazel TG, Collazo D, McKay RD (1995) Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons. Neuron 15:105–114
Wagner JP, Black IB, Cicco-Bloom E (1999) Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci 19:6006–6016
Wanaka A, Milbrandt J, Johnson EM Jr (1991) Expression of FGF receptor gene in rat development. Development 111:455–468
Weiss S, Reynolds BA, Vescovi AL, Morshead C, Craig CG, van der Kooy D (1996) Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 19:387–393
Wise PM (2003) Creating new neurons in old brains. Sci Aging Knowl Environ 2003:E13
Yazaki N, Hosoi Y, Kawabata K, Miyake A, Minami M, Satoh M, Ohta M, Kawasaki T, Itoh N (1994) Differential expression patterns of mRNAs for members of the fibroblast growth factor receptor family, FGFR-1-FGFR-4, in rat brain. J Neurosci Res 37:445–452
Yoshimura S, Takagi Y, Harada J, Teramoto T, Thomas SS, Waeber C, Bakowska JC, Breakefield XO, Moskowitz MA (2001) FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci USA 98:5874–5879
Zhao M, Li D, Shimazu K, Zhou YX, Lu B, Deng CX (2007) Fibroblast growth factor receptor-1 is required for long-term potentiation, memory consolidation, and neurogenesis. Biol Psychiatry 62:381–390
Zheng W, Nowakowski RS, Vaccarino FM (2004) Fibroblast growth factor 2 is required for maintaining the neural stem cell pool in the mouse brain subventricular zone. Dev Neurosci 26:181–196
Zitnik G, Martin GM (2002) Age-related decline in neurogenesis: old cells or old environment? J Neurosci Res 70:258–263
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This article is dedicated to the special issue Brain Plasticity: Aging and Neuropychiatric Disorders.
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Mudò, G., Bonomo, A., Di Liberto, V. et al. The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain. J Neural Transm 116, 995–1005 (2009). https://doi.org/10.1007/s00702-009-0207-z
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DOI: https://doi.org/10.1007/s00702-009-0207-z