A new role for TIMP-1 in modulating neurite outgrowth and morphology of cortical neurons.
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.
Ould-yahoui
Adlane
A
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR 6184, Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France.
Tremblay
Evelyne
E
Sbai
Oualid
O
Ferhat
Lotfi
L
Bernard
Anne
A
Charrat
Eliane
E
Gueye
Yatma
Y
Lim
Ngee Han
NH
Brew
Keith
K
Risso
Jean-Jacques
JJ
Dive
Vincent
V
Khrestchatisky
Michel
M
Rivera
Santiago
S
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
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