Mice lacking protease nexin-1 show delayed structural and functional recovery after sciatic nerve crush.
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.
Lino
Maria Maddalena
MM
Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
Atanasoski
Suzana
S
Kvajo
Mirna
M
Fayard
Bérengère
B
Moreno
Eliza
E
Brenner
Hans Rudolf
HR
Suter
Ueli
U
Monard
Denis
D
D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009409:Nerve Crush / Q000379:methods; D009416:Nerve Regeneration / Q000502:physiology; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D020127:Recovery of Function / Q000502:physiology*; D012583:Schwann Cells / Q000201:enzymology / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D020426:Sciatic Neuropathy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*
D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface