Abstract
The processes of stem cell proliferation and differentiation during embryogenesis are governed by transcription factors that regulate the regional differentiation of the central nervous system (CNS). Do neural “stem” cells persisting in the postnatal CNS disobey this sequence of events? The division of neural progenitor cells is promoted by basic Fibroblast Growth Factor Fgf2 or Epidermal Growth Factor Egf. However, while the intraventricular administration of FgF2 during embryogenesis increases the generation of cortical pyramidal neurons, the same treatment in the adult CNS produces interneurons of the olfactory bulb. The competence of neural progenitor cells to respond to Fgf is dictated by nuclear transcription factors that constrain neuronal fates through time. Developmentally regulated transcriptional programs are regulated by cell interactions, as dividing cells check their molecular signature against that of their environment. Thus, cell surface interactions account for competitive phenomena among pools of cells, including the inhibitory effect of neurons on the division of their progenitors, and may also explain the “permissive” effects of non-CNS environments. The challenge remains to understand the genetic programs that control the fate of progenitor cells within the postnatal CNS and their regulation by stress, apoptosis and environmental perturbations. These programs are likely to be similar to gene cascades that control proliferation, differentiation and migration of progenitor cells at earlier stages of development.
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References
Altman J . (1962): Are new neurons formed in the brains of adult mammals? Science 135: 1127–1128
Altman J, Das GD . (1966): Autoradiographic and histological studies of postnatal neurogenesis. J Comparative Neurology 126: 337–389.
Alvarez-Buylla A, Kirn JR . (1997): Birth, migration incorporation, and death of vocal control neurons in adult songbirds. J Neurobiol 33: 585–601
Anderson DJ . (2001): Stem Cells and Pattern Formation in the Nervous System: The Possible versus the Actual. Neuron 30: 19–35
Bayer SA, Yackel JW, Puri PS . (1982): Neurons in the rat dentate gyrus granular layer substantially increase during juvenile and adult life. Science 216: 890–892
Beddington RSP, Robertson EJ . (1999): Axis development and early asymmetry in mammals. Cell 96: 195–209
Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL . (1999): Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283: 534–537
Bremner JD, Narayan M . (1998): The effects of stress on memory and the hippocampus throughout the life cycle: implications for childhood development and aging. Development and Psychopathology 10: 871–886
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS . (2000): Hippocampal volume reduction in major depression. Am J Psychiatry 157: 115–118
Bremner JD, Randall PR, Scott TM, Bronen RA, Delaney RC, Seibyl JP, Southwick SM, McCarthy G, Charney DS, Innis RB . (1995): MRI-based measurement of hippocampal volume in posttraumatic stress disorder. Am J Psychiatry 152: 973–981
Calof AL, Rim PC, Askins KJ, Mumm JS, Gordon MK, Iannuzzelli P, Shou J . (1998): Factors regulating neurogenesis and programmed cell death in the mouse olfactory epithelium. Ann N Y Acad Sci 855: 226–229
Cameron HA, McKay R . (2001): Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435: 406–417
Cameron HA, Tanapat P, Gould E . (1998): Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus through a common pathway. Neuroscience 82: 349–354
Cameron HA, Wooley CS, McEwen BS, Gould E . (1993): Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56: 337–344
Craig CG, Morshead CM, Roach A, van der Kooy D . (1994): Evidence for a relatively quiescent stem cell in the adult mammalian forebrain. J Cell Biochem 18: 176
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
Crossley PH, Martinez S, Martin GR . (1996): Midbrain development induced by FGF8 in the chick embryo. Nature 380: 66–68
Davis AD, Temple S . (1994): A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372: 263–266
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
Duman RS, Malberg J, Thorne J . (1999): Neural plasticity to stress and antidepressant treatment-role of BDNF. Biol Psychiatry 46: 1181–1191
Duman RS, Nakagawa S, Malberg J . (2001): Regulation of adult neurogenesis by antidepressant treatment. 25: 836–844
Endoh M, Pulsinelli WA, Wagner JA . (1994): Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor. Brain Res MolBrain Res 22: 76–88
Ericson J, Rashbass P, Shedl A, Brenner-Morton S, Kawakami A, van Heyningen V, Jessel TM, Briscoe J . (1997): Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell 90: 169–180
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH . (1998a): Neurogenesis in the adult human hippocampus. Nat Med 4: 1313–1317
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH . (1998b): Neurogenesis in the adult human hippocampus. Nat Med 4: 1313–1317
Frantz GD, Weimann JM, Levin ME, McConnell SK . (1994): Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum. J Neurosci 14: 5725–5740
Frautschy SA, Walicke PA, Baird A . (1991): Localization of basic fibroblast growth factor and its mRNA after CNS injury. Brain Res 553: 291–299
Galli R, Borello U, Gritti A, Minasi MG, Bjornson C, Coletta M, Mora M, De Angelis MG, Fiocco R, Cossu G, Vescovi AL . (2000): Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci 3: 986–991
Ganat Y, Soni S, Chacon M, Schwartz ML, Vaccarino FM . (submitted) Chronic hypoxia upregulates Fibroblast Growth Factor (Fgf) ligands in the perinatal brain and induces Fgf-responsive radial glial cells in the subependymal zone. Neuroscience.
Gould E, Tanapat AJ . (1997): Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80: 427–436
Gould E, Cameron HA . (1996): Regulation of neuronal birth, migration and death in the rat dentate gyrus. Dev Neurosci 18: 22–35
Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E . (1998): Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad SciUSA 95: 3168–3171
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ . (1999): Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2: 260–265
Gurdon JB . (1988): A community effect in animal development. Nature 336: 772–774
Gurdon JB, Lemaire P, Kato K . (1993): Community effects and related phenomena in development. Cell 75: 831–834
Hara Y, Tooyama I, Akiyama H, McGeer PL, Handa J, Kimura H . (1994): Acidic fibroblast growth factor-like immunoreactivity in rat brain following cerebral infarction. Brain Res 664: 101–107
Hemmati-Brivanlou A, Melton D . (1997): Vertebrate embryonic cells will become nerve cells unless told otherwise. Cell 88: 13–17
Hongo I, Kengaku M, Okamoto H . (1999): FGF signaling and the anterior neural induction in Xenopus. Devel Biol 216: 561–581
Hunter KE, Hatten ME . (1995): Radial glial cell transformation to astrocytes is bidirectional: regulation by a diffusible factor in embryonic forebrain. Proc Natl Acad Sci USA 92: 2061–2065
Hynes M, Porter JA, Chiang C, Chang D, Tessier-Lavigne M, Beachy PA, Rosenthal A . (1995): Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 15: 35–44
Jessel TM, Lumsden A . (1997): Inductive signals and the assignment of cell fate in the spinal cord and hindbrain. In Cowan WM, Jessel TM, Zipursky SL (eds), Molecular and cellular approaches to neural development. Oxford, Oxford University Press, pp 290–333
Johansson CB, Momma S, Clarke DL, Risling M, Lendhal U, Frisen J . (1999): Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96: 25–34
Kempermann G, Gage FH . (2000): Experience-dependent regulation of adult hippocampal neurogenesis: Effects of long-term stimulation and stimulus withdrawal. Hippocampus 9: 321–332
Korada S, Zheng W, Basilico C, Schwartz ML, Vaccarino FM . (submitted): Fgf2 is necessary for the growth of glutamate projection neurons in the anterior neocortex. J Neurosci
Kornack DR, Rakic P . (1999): Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proc Natl Acad Sci USA 96: 5768–5773
Kuhn HG, Winkler J, Kempermann G, Thal L, 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
Laywell E, Rakic P, Kukekov VG, Holland EC, Steindler DA . (2000): Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci USA 97: 13883–13888
Lee SMK, Danielian PS, Fritzsch B, McMahon AP . (1997): Evidence that FGF8 signaling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Development 124: 959–969
Lim DA, Fishell GJ, Alvarez-Buylla A . (1997): Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis. Proc Natl Acad Sci USA 94: 14832–14836
Liu A, Joyner AL . (2001): EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Development 128: 181–191
Liu A, Losos K, Joyner AL . (1999): FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development 126: 4827–4838
Liu J, Solway K, Messing RO, Sharp FR . (1998): Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18: 7768–7778
Lois C, Alvarez-Buylla A . (1993): Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. ProcNatl AcadSciUSA 90: 2074–2077
Lumsden A . (1991): Cell lineage restrictions in the chick embryo hindbrain. [Review]. Phil Trans R Soc Lond 331: 281–286
Luskin MB . (1993): Restricted proliferation and migration of postnatally generated neurons derived from the forebrain ventricular zone. Neuron 11: 173–189
Magavi SS, Macklis JD . (2001): Manipulation of neural precursors in situ: induction of neurogenesis in the neocortex of adult mice. Neuropsychopharmacology 25: 816–835
Malatesta P, Harfuss E, Gotz M . (2000): Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127: 5253–5263
Malberg JE, Eissch AJ, Nestler EJ, Duman RS . (1999): Chronic antidepressant administration increases granule cell neurogenesis. Society for Neuroscience Abstract 25: 1029
Markakis EA, Gage FH . (1999): Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vescicles. J Compar Neurol 406: 449–460
Martens DJ, Tropepe V, van der Kooy D . (2000): Separate proliferation kinetics of fibroblast growth factor-responsive and epidermal growth factor-responsive neural stem cells within the embryonic forebrain germinal zone. J Neurosci 20: 1085–1095
Martinez S, Crossley PH, Cobos I, Rubenstein JLR, Martin GR . (1999): FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 126: 1189–1200
Mayer-Proeschel M, Kalyani AJ, Mujtaba T, Rao MS . (1997): Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial cells. Neuron 19: 773–785
McConnell SK . (1990): The specification of neuronal identity in the mammalian cerebral cortex. Experientia 46: 922–929
McKay R . (1997): Stem cells in the central nervous system. Science 276: 66–71
McMahon A, Bradley A . (1990): The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62: 1073–1085
Meyers EN, Lewandoski M, Martin GR . (1998): An Fgf8 mutant allelic series generated by Cre-and Flp-mediated recombination. Nature Gen 18: 136–141
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: 2251–2268
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 subependimal cells. Neuron 13: 1071–1082
Niwa H, Miyazaki J, Smith AG . (2000): Quantitative expression of Oct-3/4 defines differentiation, de-differentiation or self-renewal of ES cells. Nature Gen 24: 372–376
Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR . (2001): Neurons derived from radial glial cells establish radial units in neocortex. Nature 409: 714–720
Olsson M, Campbell K, Turnbull DH . (1997): Specification of mouse telencephalic and mid-hindbrain progenitors following heterotopic ultrasound-guided embryonic transplantation. Neuron 19: 761–772
Ongur D, Drevets WC, Price JL . (1998): Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad SciUSA 95: 13290–13295
Ornitz D, Itoh N . (2001): Fibroblast growth factors. Genome Biology 2: 3005–3012
Ortega S, Ittmann M, Tsang SH, Ehrich M, Basilico C . (1998): Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA 95: 5672–5677
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
Pownall ME, Tucker AS, Slack JMW, Isaacs HV . (1996): eFGF, Xcad3 and Hox genes form a molecular pathway that establishes the anteroposterior axis in Xenopus. Development 122: 3881–3892
Puelles L, Rubenstein JL . (1993): Expression patterns of homeobox and other putative regulatory genes in the embryonic mouse forebrain suggest a neuromeric organization. TINS 16: 472–479
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
Rajkowska G, Miguel-Hildago JJ, Wei J, Dilley G, Pittman SD, Melzer HY, Overholser JC, Roth BL, Stockeimer CA . (1999): Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45: 1085–1098
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
Reynolds BA, Weiss S . (1992): Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255: 1707–1710
Reynolds BA, Tetzlaff W, Weiss S . (1992): A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12: 4565–4574
Richards LJ, Kilpatrick TJ, Bartlett PF . (1992): De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 89: 8591–8595
Ridet JL, Malhotra SK, Privat A, Gage FH . (1997): Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20: 570–577
Robel L, Ding M, James AJ, Lin X, Leckman JF, Vaccarino FM . (1995): Fibroblast growth factor 2 increases Otx2 expression in precursor cells from the mammalian telencephalon. J Neurosci 15: 7879–7891
Rubenstein JLR, Shimamura K . (1997): Regulation of patterning and differentiation in the embryonic vertebrate forebrain. In Cowan WM, Jessel TM, Zipursky SL (eds), Molecular and cellular approaches to neural development, 1st ed. New York: Oxford University Press, pp 356–390
Sha PJ, Ebmeier KP, Glabus MF, Goodwin GM . (1998): Cortical gray matter reductions associated with treatment-resistant chronic unipolar depression. Arch Gen Psychiatry 527: 532
Sheen VL, Macklis JD . (1995): Targeted neocortical cell death in adult mice guides migration and differentiation of transplanted embryonic neurons. J Neuroscience 15: 8378–8392
Simeone A, Acampora D, Gulisano M, Stornaiuolo A, Boncinelli E . (1992): Nested expression domains of four homeobox genes in developing rostral brain. Nature 358: 687–690
Suhonen JO, Peterson DA, Gage FH . (1996): Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 383: 624–627
Takahashi T, Nowakowski RS, Caviness VS . (1996): The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J Neurosci 16: 6183–6196
Tanapat AJ, Hastings NB, Reeves AJ, Gould E . (1998): Estrogen stimulates the proliferation of granule cell precursors in the dentate gyrus of adult female rats. Neuroscience Abstracts 24: 796–798.
Temple S, Alvarez-Buylla A . (1999): Stem cells in the adult mammalian central nervous system. Curr Opinion Neurobiol 9: 135–141
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 developing mouse telencephalon. Devel Biol 208: 166–188
Tropepe V, Hitoshi S, Sirad C, Mak TW, Rossant J, van der Kooy D . (2001): Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron 30: 65–78
Vaccarino FM . (2000): Stem cell diversity in the developing CNS. The Neuroscientist 6: 338–352
Vaccarino FM, Schwartz ML, Hartigan D, Leckman JF . (1995): Effect of basic fibroblast growth factor on the genesis of excitatory and inhibitory neurons in primary cultures of cells from the mammalian telencephalon. Cereb Cortex 1: 64–78
Vaccarino FM, Schwartz ML, Raballo R, Rhee J, Lyn-Cook R . (1999a): Fibroblast Growth Factor signaling regulates growth and morphogenesis at multiple steps during brain development. In Pedersen RA, Shatten G (eds), Current Topics in Developmental Biology. 46 San Diego, CA, Academic Press, pp 179–200
Vaccarino FM, Schwartz ML, Raballo R, Nilsen J, Rhee J, Zhou M, Doetschman T, Coffin JD, Wyland JJ, Hung Y-TE . (1999b): Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis. Nat Neurosci 2: 246–253
Whittemore SR . (2000): Immortalized neural cell lines for CNS transplantation. Prog Brain Res 127: 49–65
Yoshimura S, Takagi Y, Harada J, Teramoto T, Thomas SS, Waeber C, Bakowska J, Breakefield XO, Moskowitz MA . (2001): FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci USA 98: 5874–5879
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Vaccarino, F., Ganat, Y., Zhang, Y. et al. Stem Cells in Neurodevelopment and Plasticity. Neuropsychopharmacol 25, 805–815 (2001). https://doi.org/10.1016/S0893-133X(01)00349-9
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DOI: https://doi.org/10.1016/S0893-133X(01)00349-9
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