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Neuroscience Graduate Program at UCSF
Birth and Migration of New Neurons
My laboratory is interested in the mechanism and function of adult neurogenesis. We would like to understand neuronal birth, migration and differentiation in adult brains. In addition, we are interested in how new nerve cells are integrated and contribute to the function of adult brain circuits. On the last few years we have focused our work on the identification of the neural stem cells that function as the primary neuronal precursors in the adult brain. This lead to a surprising conclusion.
We initially identified a region (SVZ) in the brain of adult mammals, close to the walls of the lateral ventricles, containing large numbers of neuronal precursors. Subsequently, we demonstrated that young neurons born in this brain region migrate a long distance through the anterior forebrain to complete their differentiation and become integrated in the olfactory bulb. This migration happens constantly and at a very high rate. Further work on this system led us to identify a novel form of neuronal translocation, called chain migration. This migration is unique in that young neurons move without the aid of radial glial or axonal guides. Instead, young neurons migrate closely associated to each other, forming long aggregates called chains. We have shown that there is a very extensive network of chains of young migrating neurons in the adult brain. Investigations into the origin of these new neurons lead us to the stem cells in the SVZ. Surprisingly, these cells correspond to astrocytes. Based on this finding we have suggested a new hypothesis that links early neuroepithelial cells, radial glia and stem cells as the stem cells of the development and adult brain. Work currently underway in the laboratory is trying to test this hypothesis. In addition we are working on the following related questions:
What is the mechanism of chain migration? We would like to understand how neuronal precursors become organized into chains, how cells move in chains, what guides young neurons toward the olfactory bulb and where else in the adult and embryonic brain chain migration occurs.
What kinds of astrocytes can function as stem cells? We are in search for better markers, in the embryo and in the adult, for neural stem cells. We are studying the molecular signals that regulate the proliferation and differentiation of neural stem cells.
What is the function of neurons formed in the adult brain and how do olfactory learning and olfactory discrimination affect neuronal recruitment in the olfactory bulb? We are interested in behavioral or hormonal conditions that affect neuronal replacement in the olfactory bulb. In parallel we are developing techniques to stop neuronal production or migration to study their effects on the olfactory bulb and olfactory function.
Are neural stem cells in the postnatal brain the origin of brain tumors? We are trying to test whether brain tumors originate from the astrocytes that function as stem cells in the adult brain.
Do human SVZ astrocytes have neural stem cells potential? We have identified a band of stem cell astrocytes in the adult human brain. We are trying to determine the normal function of these cells.
The adult brain offers unique experimental advantages to study the mechanism of neuronal production, migration and differentiation: germinal layers contain fewer cells and are simpler in organization as compared to the embryo; neuronal production is not limited to a short window of time, but occurs over long periods; cell movements are not affected by major changes in brain structure; cells can be grafted into precise locations in the germinal layers. In addition, experimental manipulation of neuronal production, migration or survival in juveniles and adults will allow us to ask questions about the contribution of specific types of neurons to behavior and brain repair.
What is the mechanism of chain migration? We would like to understand how neuronal precursors become organized into chains, how cells move in chains, what guides young neurons toward the olfactory bulb and where else in the adult and embryonic brain chain migration occurs.
What kinds of astrocytes can function as stem cells? We are in search for better marker, in the embryo and in the adult, for neural stem cells. We are studying the molecular signals that regulate the proliferation and differentiation of neural stem cells.
What is the function of neurons formed in the adult brain and how do olfactory learning and olfactory discrimination affect neuronal recruitment in the olfactory bulb? We are interested in behavioral or hormonal conditions that affect neuronal replacement in the olfactory bulb. In parallel we are developing techniques to stop neuronal production or migration to study their effects on the olfactory bulb and olfactory function.
What is the relationship of neural stem cells to brain tumors? We are trying to test whether brain tumors originate from the astrocytes that function as stem cells in the adult brain.
The adult brain offers unique advantages to study the mechanism of neuronal production, migration and differentiation: germinal layers contain many fewer cells and are simpler in organization as compared to the embryo; neuronal production is not limited to a short window of time, but occurs over long periods; cell movements are not affected by major changes in brain structure; cells can be grafted into precise locations in the germinal layers. In addition, experimental manipulation of neuronal production, migration or survival in juveniles and adults will allow us to ask questions about the contribution of specific types of neurons to behavior and brain repair.
Link to Publications via PubMed
Wichterle, H., García-Verdugo, J.M., Herrera, D.G. and Alvarez-Buylla, A. (1999) Young neurons from medial ganglionic eminence disperse in adult and embryonic brain. Nature Neurosci. 2: 461-466.
Lim, D.A. and Alvarez-Buylla, A. (1999) Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc. Natl. Acad. Sci. USA 96: 7526-7531.
Doetsch, F., Caillé I., Lim, D.A., García-Verdugo, J.M. and Alvarez-Buylla, A. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703-716.
Lim, D. A., Tramontin, A.D., Trevejo, J.M., Herrera, D.G., Garcia-Verdugo, J.M., and Alvarez-Buylla, A. (2000) Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28: 713-726
Alvarez-Buylla, A., Garcia-Verdugo, J. M., Tramontin, A.D. (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2: 287-93
Wichterle, H., Turnbull D.H., Nery, S., Fishell, G., and Alvarez-Buylla, A. (2001) In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. Development 128: 3759-71
Seri, B., García-Verdugo, J. M., McEwen, B.S., Alvarez-Buylla, A. (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus, J. Neurosci. 21:7153-7160
Alvarez-Buylla, A., and Garcia-Verdugo, J. M. (2002) Neurogenesis in adult subventricular zone. J. Neurosci. 22: 629-634
Petreanu, L. and Alvarez-Buylla, A. (2002) Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J Neurosci. 22:6106-13
Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J.M. and Alvarez-Buylla, A. (2002) EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36:1021-1034
Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J.M., Fike, J.R., Lee, H.O., Pfeffer, K., Lois, C., Morrison, S.J. and Alvarez-Buylla, A. (2003) Fusion of bone marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968-73
Sanai, N., Tramontin, A.D., Quinones-Hinojosa, A., Barbaro, N.M., Gupta, N., Kunwar, S., Lawton, M.T., McDermott, M.W., Parsa, A.T., Garcia-Verdugo, J.M., Berger, M.S. and Alvarez-Buylla, A. (2004). Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740-44
Alvarez-Buylla A. and Lim, D.A. (2004) For the Long Run: Maintaining Germinal Niches in the Adult Brain. Neuron 41:683-686
Merkle FT, Tramontin AD, Garcia-Verdugo JM and Alvarez-Buylla A. (2004) Radial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci USA 101: 17525-32
Spassky, N., Merkle, F.T., Flamees, N., Tramontin, A., Garcia-Verdugo, J.M. and Alvarez-Buylla, A. (2005). Adult Ependymal Cells Are Postmitotic and Are Derived from Radial Glial Cells during Embyogenesis. J Neurosci. 25(1): 10-18.
Kohwi, M., Osumi, N., Rubenstein, J.L. and Alvarez-Buylla, A. (2005). Pax6 Is Required for Making Specific Subpopulations of Granule and Periglomerular Neurons in the Olfactory Bulb. J. Neurosci. 25(30) 6997-7003.
Sanai, N., Alvarez-Buylla, A. and Berger, M. (2005) Neural Stem Cells and the Origin of Gliomas. N Engl J Med 353: 811-22
Sawamoto, K., Wichterle, H., Gonzalez-Perez, O., Cholfin, J., Yamada, M., Spassky, N., Murcia, N., Garcia-Verdugo, J.M., Marin, O., Rubenstein, J., Tessier-Lavigne, M., Okano, H. and Alvarez-Buylla, A. (2006) New Neurons Follow the Flow of Cerebrospinal Fluid in the Adult Brain. Science 311(5761):629-32
Jackson, E.L., Garcia-Verdugo, J.M., Gil-Perotin, S., Roy, M., Quinones-Hinojosa, A., Vandenberg, S. and Alvarez-Buylla A. (2006) PDGFRalpha-Positive B Cells Are Neural Stem Cells in the Adult SVZ that Form Glioma-like Growths in Response to Increased PDGF Signaling. Neuron 51(2):187-99.
Menn, B., Garcia-Verdugo, J.M., Yaschine, C., Gonzalez-Perez, O., Rowitch, D. and Alvarez-Buylla, A. (2006) Origin of Oligodendrocytes in the Subventricular Zone of the Adult Brain. J Neurosci 26(30):7907-18
Arturo Alvarez-Buylla, Ph.D.
Phone
415-514-2348
Physical address
HSW-1201E
513 Parnassus
Mailing address
UCSF
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Box 0525
San Francisco, CA 94143-0525
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