title: A new role for TIMP-1 in modulating neurite outgrowth and morphology of cortical neurons.
abstract: BACKGROUND
  Tissue inhibitor of metalloproteinases-1 (TIMP-1) displays pleiotropic activities, both dependent and independent of its inhibitory activity on matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMP-1 is strongly upregulated in reactive astrocytes and cortical neurons following excitotoxic/inflammatory stimuli, but no information exists on its effects on growth and morphology of cortical neurons.
  
  
  RESULTS
  We found that 24 h incubation with recombinant TIMP-1 induced a 35% reduction in neurite length and significantly increased growth cones size and the number of F-actin rich microprocesses. TIMP-1 mediated reduction in neurite length affected both dendrites and axons after 48 h treatment. The effects on neurite length and morphology were not elicited by a mutated form of TIMP-1 inactive against MMP-1, -2 and -3, and still inhibitory for MMP-9, but were mimicked by a broad spectrum MMP inhibitor. MMP-9 was poorly expressed in developing cortical neurons, unlike MMP-2 which was present in growth cones and whose selective inhibition caused neurite length reductions similar to those induced by TIMP-1. Moreover, TIMP-1 mediated changes in cytoskeleton reorganisation were not accompanied by modifications in the expression levels of actin, betaIII-tubulin, or microtubule assembly regulatory protein MAP2c. Transfection-mediated overexpression of TIMP-1 dramatically reduced neuritic arbour extension in the absence of detectable levels of released extracellular TIMP-1.
  
  
  CONCLUSIONS
  Altogether, TIMP-1 emerges as a modulator of neuronal outgrowth and morphology in a paracrine and autrocrine manner through the inhibition, at least in part, of MMP-2 and not MMP-9. These findings may help us understand the role of the MMP/TIMP system in post-lesion pre-scarring conditions.
authors.affiliation: Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR 6184, Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France.
authors.forename: Adlane
authors.initials: A
authors.lastname: Ould-yahoui
authors.forename: Evelyne
authors.initials: E
authors.lastname: Tremblay
authors.forename: Oualid
authors.initials: O
authors.lastname: Sbai
authors.forename: Lotfi
authors.initials: L
authors.lastname: Ferhat
authors.forename: Anne
authors.initials: A
authors.lastname: Bernard
authors.forename: Eliane
authors.initials: E
authors.lastname: Charrat
authors.forename: Yatma
authors.initials: Y
authors.lastname: Gueye
authors.forename: Ngee Han
authors.initials: NH
authors.lastname: Lim
authors.forename: Keith
authors.initials: K
authors.lastname: Brew
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Risso
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.forename: Santiago
authors.initials: S
authors.lastname: Rivera
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000201:enzymology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D049452:Green Fluorescent Proteins; D020780:Matrix Metalloproteinase 9