title: The MMP-1/PAR-1 Axis Enhances Proliferation and Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells.
abstract: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a role in varied forms of developmental and postnatal neuroplasticity. MMP substrates include protease-activated receptor-1 (PAR-1), a G-protein coupled receptor expressed in hippocampus. We examined proliferation and differentiation of adult neural progenitor cells (aNPCs) from hippocampi of mice that overexpress the potent PAR-1 agonist MMP-1. We found that, as compared to aNPCs from littermate controls, MMP-1 tg aNPCs display enhanced proliferation. Under differentiating conditions, these cells give rise to a higher percentage of MAP-2(+) neurons and a reduced number of oligodendrocyte precursors, and no change in the number of astrocytes. The fact that these results are MMP and PAR-1 dependent is supported by studies with distinct antagonists. Moreover, JSH-23, an inhibitor of NF-κB p65 nuclear translocation, counteracted both the proliferation and differentiation changes seen in MMP-1 tg-derived NPCs. In complementary studies, we found that the percentage of Sox2(+) undifferentiated progenitor cells is increased in hippocampi of MMP-1 tg animals, compared to wt mice. Together, these results add to a growing body of data suggesting that MMPs are effectors of hippocampal neuroplasticity in the adult CNS and that the MMP-1/PAR-1 axis may play a role in neurogenesis following physiological and/or pathological stimuli.
authors.affiliation: Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Valente
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Allen
authors.affiliation: Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bortolotto
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Seung T
authors.initials: ST
authors.lastname: Lim
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Conant
authors.affiliation: Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Grilli
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D044463:Receptor, PAR-1; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse