title: Matrix metalloproteinase-9 regulates survival of neurons in newborn hippocampus.
abstract: The number of neurons in the adult rodent brain is strongly influenced by events in early postnatal life that eliminate approximately half of the neurons. Recently, we reported that neurotrophins induced survival of neonatal rat hippocampal neurons by promoting neural activity and activation of the Ser/Thr kinase, Akt. The survival of neurons also depended on integrin signaling, but a role for the extracellular matrix (ECM) in this mechanism was yet to be explored. Here, we show that levels of the matrix metalloproteinase-9 (MMP9) decrease, and the level of the ECM protein laminin increases in rat hippocampus during the period of neuronal death. Hippocampi from MMP9 null mice showed higher levels of laminin expression than wild type at P1 and no further increase at P10. In vitro, the matrix metalloproteinase inhibitor FN-439 promoted survival of neurons in a laminin-integrin β1-dependent manner. Blocking laminin signaling attenuated activation of Akt by depolarization. In vivo, injecting FN-439 into the neonatal hippocampus increased the level of laminin and promoted neuronal survival through an integrin-dependent mechanism. These results show signals from the ECM are not simply permissive but rather actively regulated, and they interact with neuronal activity to control the number of hippocampal neurons. This work is the first to report a role for MMP9 in regulating neuronal survival through the developmental process that establishes the functional brain.
authors.affiliation: Laboratory of Molecular Biology, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA. sachikom@ninds.nih.gov
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKay
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D002452:Cell Count; D016764:Cell Polarity; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology / Q000254:growth & development; D006877:Hydroxamic Acids / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats
chemical_list: C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; D006877:Hydroxamic Acids; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat