title: Noggin expands neural stem cells in the adult hippocampus.
abstract: 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.
authors.affiliation: Davee Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois 60611, USA. mbonagu1@jhmi.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bonaguidi
authors.forename: Chian-Yu
authors.initials: CY
authors.lastname: Peng
authors.forename: Tammy
authors.initials: T
authors.lastname: McGuire
authors.forename: Gustave
authors.initials: G
authors.lastname: Falciglia
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Gobeske
authors.forename: Catherine
authors.initials: C
authors.lastname: Czeisler
authors.forename: John A
authors.initials: JA
authors.lastname: Kessler
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D007065:Idoxuridine / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019081:O Antigens / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D012794:Sialic Acids / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D003857:Deoxyuridine; D005904:Glial Fibrillary Acidic Protein; D007065:Idoxuridine; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D039842:Neural Cell Adhesion Molecule L1; D016900:Neurofilament Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D019081:O Antigens; D010751:Phosphopyruvate Hydratase; D012794:Sialic Acids; D019098:Telomerase; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C079240:Mtap2 protein, mouse; C103469:polysialyl neural cell adhesion molecule; C012244:5-chloro-2'-deoxyuridine; C509187:Tert protein, mouse
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