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The Journal of Neuroscience, April 4, 2007, 27(14):3677-3685; doi:10.1523/JNEUROSCI.0277-07.2007

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Development/Plasticity/Repair
Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Maria Maddalena Lino,¹ Suzana Atanasoski,^2,3 Mirna Kvajo,¹ Bérengère Fayard,¹ Eliza Moreno,¹ Hans Rudolf Brenner,⁴ Ueli Suter,² and Denis Monard¹

¹Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland, ²Institute of Cell Biology, Swiss Federal Institute of Technology Zurich, CH-8093 Zurich, Switzerland, and ³Department of Clinical-Biological Sciences, Institute of Physiology, and ⁴Institute of Physiology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland

Correspondence should be addressed to Prof. Denis Monard, Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Email: denis.monard{at}fmi.ch

Multiple molecular mechanisms influence nerve regeneration. Because serine proteases were shown to affect peripheral nerve regeneration, we performed nerve crush experiments to study synapse reinnervation in adult mice lacking the serpin protease nexin-1 (PN-1). PN-1 is a potent endogenous inhibitor of thrombin, trypsin, tissue plasminogen activators (tPAs), and urokinase plasminogen activators. Compared with the wild type, a significant delay in synapse reinnervation was detected in PN-1 knock-out (KO) animals, which was associated with both reduced proliferation and increased apoptosis of Schwann cells. Various factors known to affect Schwann cells were also altered. Fibrin deposits, tPA activity, mature BDNF, and the low-affinity p75 neurotrophin receptor were increased in injured sciatic nerves of mutant mice. To test whether the absence of PN-1 in Schwann cells or in the axon caused delay in reinnervation, PN-1 was overexpressed exclusively in the nerves of PN-1 KO mice. Neuronal PN-1 expression did not rescue the delayed reinnervation. The results suggest that Schwann cell-derived PN-1 is crucial for proper reinnervation through its contribution to the autocrine control of proliferation and survival. Thus, the precise balance between distinct proteases and serpins such as PN-1 can modulate the overall impact on the kinetics of recovery.

Key words: protease nexin-1; Schwann cell; BDNF; fibrin; nerve crush; serine proteases

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Received Sept. 26, 2006; revised Feb. 19, 2007; accepted Feb. 27, 2007.

Correspondence should be addressed to Prof. Denis Monard, Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Email: denis.monard{at}fmi.ch

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