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The Journal of Neuroscience, September 10, 2008, 28(37):9194-9204; doi:10.1523/JNEUROSCI.3314-07.2008
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Development/Plasticity/Repair
Noggin Expands Neural Stem Cells in the Adult Hippocampus
Michael A. Bonaguidi,1,2,3 * Chian-Yu Peng,1 * Tammy McGuire,1 Gustave Falciglia,1,4 Kevin T. Gobeske,1 Catherine Czeisler,1,5 andJohn A. Kessler1 1Davee Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois 60611, 2Institute for Cell Engineering and 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 4Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, and 5Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158
Correspondence should be addressed to Michael A. Bonaguidi, 733 North Broadway, #706, Baltimore, MD 21205. Email: mbonagu1{at}jhmi.edu
New neurons are added to the adult hippocampus throughout life and contribute to cognitive functions, including learning and memory. It remains unclear whether ongoing neurogenesis arises from self-renewing neural stem cells (NSCs) or from multipotential progenitor cells that cannot self-renew in the hippocampus. This is primarily based on observations that neural precursors derived from the subventricular zone (SVZ) can be passaged long term, whereas hippocampal subgranular zone (SGZ) precursors are rapidly depleted by passaging. We demonstrate here that high levels of bone morphogenetic protein (BMP) signaling occur in hippocampal but not SVZ precursors in vitro, and blocking BMP signaling with Noggin is sufficient to foster hippocampal cell self-renewal, proliferation, and multipotentiality using single-cell clonal analysis. Moreover, NSC maintenance requires continual Noggin exposure, which implicates BMPs as crucial regulators of NSC aging. In vivo, Noggin is expressed in the adult dentate gyrus and limits BMP signaling in proliferative cells of the SGZ. Transgenic Noggin overexpression in the SGZ increases multiple precursor cell populations but proportionally increases the glial fibrillary acidic protein-positive cell population at the expense of other precursors, suggesting that Noggin acts on NSCs in vivo. To confirm this, we used a dual thymidine analog paradigm to repeatedly label slowly dividing cells over a long duration. We find that small populations of label-retaining cells exist in the SGZ and that Noggin overexpression increases their numbers. Thus, we propose that the adult hippocampus contains a population of NSCs, which can be expanded both in vitro and in vivo by blocking BMP signaling.
Key words: hippocampus; progenitor; bone morphogenetic protein; neurogenesis; development; aging
Received July 21, 2007; revised July 7, 2008; accepted July 27, 2008.
Correspondence should be addressed to Michael A. Bonaguidi, 733 North Broadway, #706, Baltimore, MD 21205. Email: mbonagu1{at}jhmi.edu
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[Abstract] [Full Text] [PDF]
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