Fred Gage

Fred Gage, Ph.D., The Salk Institute for Biological Studies
 
 
 



Song H, Stevens CF, Gage FH. 2002. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nature Neuroscience. (5)5: 438-445.



Song H, Stevens C, Gage FH. 2002. Astroglia induce neurogenesis from adult neural stem cells. Nature. (417): 39-44.



Vallieres L, Campbell IL, Gage FH, Sawchenko PE. 2002. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of Interleukin-6. The Journal of Neuroscience. 22(2): 486-492.



van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. 2002. Functional neurogenesis in the adult hippocampus. Nature. (415): 1030-1034.



Zhao X, Lein ES, He A, Smith S, Aston C, Gage FH.2001. Transcriptional profiling reveals strict boundaries between hippocampal subregions. Journal of Comparative Neurology. (441): 187-196.



Pfeifer A, Brandon EP, Koostra N, Gage FH, Verma IM. 2001. Delivery of the Cre recombinase by a self-deleting lentiviral vector: Efficient gene targeting in vivo. Proceedings of National Academy of Sciences. (98)20:11450-11455.



Gage FH. 2000.  Mammalian neural stem cells.  Science. (287): 1433-1438.



Horner PJ, Power AE, Kempermann G, Kuhn HG, Palmer TD, Winkler J, Thal LJ and Gage FH. 2000. Proliferation and differentiation of progenitor cells throughout the intact rat spinal cord.  J. Neurosci. 20 (6): 2218-2228.



Kafri T, Van Praag H, Gage FH and Verma IM. 2000.  Lentiviral vectors: Regulated gene expression.  Molecular Therapy. 1(6): 516-521.



Shihabuddin LS, Horner PJ, Ray J, Gage FH. 2000. Adult spinal cord stem cells generate after transplantation in adult dentate gyrus. J. Neurosci. 20 (23): 8727-8735.



Taupin P, Ray J, Fischer WH, Suhr ST, Hakansson K, Grubb A, Gage FH. 2000. FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine factor. Neuron. (28): 385-397.



van Praag H, Kempermann G and Gage FH. 2000.Neural consequences of environmental enrichment.  Nature Review Neuroscience. (1): 191-198.



Young MJ, Ray J, Whiteley SJO, Klassen H and Gage FH. 2000. Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats.  Molecular and Cellular Neuroscience. (16): 197-205.



Kafri T, Van Praag H, Ouyang L, Gage FH and Verma IM. 1999. A packaging cell line for lentivirus vectors.  Journal of Virology. 73(1): 576-584.



McDonald JW and the Research Consortium of the Christopher Reeve Paralysis Foundation. 1999.  Repairing the damaged spinal cord. Scientific American. (281): 64-73.



van Praag H, Christie BR, Sejnowski TJ and Gage FH. 1999. Running enhances neurogenesis, learning and long-term potentiation in mice. Proc. Natl. Acad. Sci. 96 (23): 13427-13431.



van Praag H, Kempermann G and Gage FH. 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.  Nature Neuroscience. 2(3): 266-270.





Aubert I, Ridet J-L, Schachner M, Rougon G and Gage FH. 1998. Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation.  The Journal of Comparative Neurology. (399): 1-9.



McTigue DA, Horner PJ, Stokes BT and Gage FH. 1998. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord.  J. Neurosci. 18(14): 5354-5365.



Fagan AM, Suhr ST, Lucidi-Phillipi CA, Peterson DA, Holtzman DM, and Gage  FH. 1997. Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus.  The J. Neurosci. 17(7): 2499-2511.



Kempermann G, Kuhn HG, and Gage FH. 1997. More hippocampal neurons in adult mice living in an enriched environment. Nature. (386): 493-495.



Palmer TD, Takahashi J. and Gage FH.  1997. The adult rat hippocampus contains primordial neural stem cells.  Molecular and Cellular Neuroscience. (8): 389-404.



Peterson D, Leppert JT, Lee KF, and Gage FH. 1997. Basal forebrain neuronal loss in mice lacking neurotrophin receptor p75. Science. (277):837-838.



Ray J, Baird A, and Gage FH. 1997. A 10-amino acid sequence of fibroblast growth factor 2 is sufficient for its mitogenic activity on neural progenitor cells. Proc. Natl. Acad. Sci. USA. (94): 7047-7052.



Raymon HK, Thode S, and Gage FH. 1997. Application of ex vivo gene therapy in the treatment of Parkinson抯 disease.  Experimental Neurology.  (144): 82-91.



Sah DWY, Ray J, and Gage FH. 1997. Regulation of voltage- and ligand-gated currents in rat hippocampal progenitor cells in vitro. J. Neurobiology. (32): 95-110.



Senut MC, Aubert I, Horner PJ, and Gage FH. 1997. Gene Transfer for Adult CNS Regeneration and Aging. In: Gene Transfer and Therapy for Neurobiological Disorders. Umana Press, E.A. Choicca and X.O. Brakefield editors. Ch 17, pg 341-371.



Suhonen JO,  eterson DA, Ray J and Gage FH.  1996. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature. (383): 624-627.
 
 

The Salk Institute for Biological Studies

Fred H. Gage

Ph.D. The Johns Hopkins University, 1976



gage@salk.edu





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Regeneration and Neurogenesis in the Adult Mammalian Nervous System

The focus of research in this laboratory is on degeneration and regeneration in the adult central nervous system.



The adult CNS neurons have been considered post-mitotic and refractory to regeneration. Recent findings challenge this doctrine. Evidence now supports the assertion that stem cells reside within the adult brain, which may act as a source for neurogenesis in restricted sites of the adult brain. Our aim is to identify the cellular and molecular factors which control the proliferation, migration, and differentiation, and determine the fate of the adult neuron stem cells.



In addition, the adult CNS has also been characterized as resistant to regeneration because of the absence of required growth factor and substrate molecules present during development. Our goals are to define spatial and temporal conditions that permit functional regeneration in the adult nervous system.



van Praag, H., Kempermann, G. and Gage, F.H. Neural consequences of enrichment. Nature Review Neuroscience, in press, 2000.





Horner, P.J. and Gage, F.H. Regenerating the damaged central nervous system. Nature, 407: 963-970, 2000.





Taupin, P., Ray, J., Fischer, W.H., Suhr, S.T. and Gage, F.H. FGF-2 responsive neural stem cell proliferation requires CCg, an autocrine/paracrine co-factor. Neuron, in press, 2000.





Gage, F.H. Mammalian neural stem cells. Science, 287: 1433-1438, 2000.





Sakurada, K., Ohshima-Sakurada, M., Palmer, T.D. and Gage, F.H. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development, 126(18): 4017-4026, 1999.



http://www.salk.edu/faculty/gage.html

FRED H. GAGE

Professor, Laboratory of Genetics, The Salk Institute
 Degrees and Awards:

Ph.D., The Johns Hopkins University, 1976. Fogarty International Fellowship (NSF), 1980. McKnight Foundation Development Award, 1987. PEW Foundation Neurosciences Program Award, 1986. Bristol-Myers Squibb Neurosciences Research Award, 1987. IPSEN prize in Neuronal Plasticity, 1990. Ameritec Prize, 1992. Dana Award, 1993.  

Research Interests:

Investigate mechanism of cell death and regeneration to induce recovery of function following brain damage. For the cells of the brain or spinal cord which are seriously injured and non-functional, but have not died and disappeared, the strategy is to deliver the appropriate trophic factor to the appropriate site in the brain, with the aim of revitalizing the cells and training or teaching them to function appropriately again. For the cells that have died and disappeared, the strategy requires the transplantation or generation of new cells to the CNS and teach or train these new cells to function appropriately. In addition to fetal cells, genetically engineering cells are used to create a clonal donor cell with all the properties necessary to replace the missing function of the dead cells.
 

Fred Gage

Professor of Biology, The Salk Institute

e-mail: fgage@salk.edu  



REGENERATION IN THE ADULT MAMMALIAN NERVOUS SYSTEM
     The focus of research in this laboratory is on the development of strategies to induce recovery of function following central nervous system (CNS) damage. These strategies are predicated on understanding the basic neurobiological processes which underlie neuronal plasticity.  



NEURONAL REGENERATION AND GENE TRANSFER  
     We have attempted to establish reliable and rational procedures to repair or replace neurotransmitter function following damage to the adult brain and spinal cord by focusing on a few closely related transmitter systems that are clearly involved in measurable behaviors in experimental animals and humans. Our underlying premise is that transfer to the brain of genes that will

either protect against neuronal cell death, repair neuronal cell damage, or replace missing neurons’ transmitter function will delay functional decline or reverse some of the deficits associated with neurodegeneration.  


     rogress toward gene therapy for the damaged and diseased central nervous system is progressing rapidly, but this progress parallels and is predicated on the more complete understanding of how the intact brain functions. A summary of recent results are listed below.  


     1. We have demonstrated by grafting genetically engineered cells expressing NGF into the adult and aged brain that NGF by itself is adequate to protect against neuronal death induced by axotomy or by aging. Further, we have shown that NGF can induce axon elongation of cholinergic neurons, that these growing axons are guided by astrocytes toward their target, and that the astrocytes express PSA-NCAM on their membrane surface when axons are growing on them. Finally, we have shown that the regeneration observed can be functional to the extent that some behaviors are restored which were lost due to aging or damage.  


     2. FGF-2 is a pluripotent trophic factor that exists in the adult brain. The receptor for FGF-2, and FGFR1, is present on many neurons in the adult brain. Hippocampal projecting glutamate neurons of the entorhinal cortex express this receptor and, after axotomy, die and degenerate. We have engineered primary fibroblast to express FGF-2 on their surface and then grafted these cells near the site of cell death.  


     3. We have designed cells to make and secrete acetylcholine and implanted these cells into either the cortex or hippcampus, following brain damage and aging, and have determined that acetylcholine mediates different types of learning depending on the site of action.  



NEUROGENESIS AND CELL REPLACEMENT  
     1. We are optimizing procedures to isolate and expand progenitor cells of the adult hippocampus in vitro under defined conditions. We have isolated individual cells of the expanded population of the progenitor cells and grown them as clones to determine the pluripotentiality of the progeny of each of the clones. Finally, we are beginning to define conditions that can direct the fate of the progenitor cells toward glial or neuronal lineage.  


     2. We have begun to determine that adult progenitors survive engraftment to the developing and adult brain. We are beginning to reveal the exogenous and endogenous factors that influence the extent of cell survival.


     3. We have now isolated and expanded progenitor cells from other areas of the adult brain. We compared the growth patterns and phenotypes of progenitors from the different brain areas, to determine that a common progenitor cell exists. We have grafted these isolated and characterized progenitor cells to different areas of the adult nervous system to determine if they respond in a similar or different way to local cues, to differentiate into glia and neurons.  


     4. Presently, we are implanting the cells into the damaged CNS to determine if they can participate in the repair process or replace missing cells. Independently of our success in the preceding experiments, we will genetically engineer the progenitor cells to make and secrete the product, then implant the cells into a relevant animal model. Finally, we are injecting FGF-2 chronically in the adult brain to induce proliferation and differentiation of the endogenous progenitor cells.  





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      Lucici-Phillipi, C.A., Clary, D.O., Reichardt, L.F., and Gage, F.H. (1996). TrkA activation is sufficient to rescue axotomized cholinergic neurons. Neuron 16: 1-20.
      Peterson, D.A., Lucidi-Phillipi, C.A., Murphy, D.P., Ray, J., and Gage, F.H. (1996). FGF-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death. Journal of Neuroscience 16(3): 886-898.  


      Naldini, L., Blomer, U., Gallay, Pl, Gage, F.H., Verma, I.M., and Trono, D. (1996). In vivo gene delivery and stable transduction of postmitotic cells by a lentiviral vector. Science 272: 263-267.  


      Nakajima, T., Fukamizu, A., Takahashi, J., Gage, F.H., Fisher, T., Blenis, J. and Montminy, M. (1996). The signal dependent co-activator CBP is a nuclear target for pp90RSK. Cell 86: 465-474.  


      Suhonen, J.O., Peterson, D.A., Ray, J. and Gage, F.H. (1996). Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature, in press.  







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Fred Gage received his Ph.D. from Johns Hopkins University. Awards include the Christopher Reeves Medal, a MERIT award from the National Institutes of Health, and a Decade of the Brain Medal.