Mice lacking protease nexin-1 show delayed structural and functional recovery after sciatic nerve crush

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Serine proteases play a role in peripheral nerve regeneration.
• Nexin-1 (PN-1) is an endogenous inhibitor of proteases like thrombin and tPA.
• Schwann cells are critical for nerve repair and regeneration.

Purpose of the Study:

• To investigate the role of PN-1 in synapse reinnervation after peripheral nerve injury.
• To determine whether PN-1 deficiency affects Schwann cell behavior during nerve regeneration.
• To elucidate the cell-specific function of PN-1 in nerve repair.

Main Methods:

• Nerve crush experiments were performed on adult mice lacking PN-1 (PN-1 knock-out, KO).
• Synapse reinnervation was assessed in PN-1 KO and wild-type mice.
• PN-1 was selectively overexpressed in neurons or exclusively in nerves of PN-1 KO mice to test cell-specific roles.
• Schwann cell proliferation and apoptosis were quantified.

Main Results:

• PN-1 KO mice exhibited a significant delay in synapse reinnervation compared to wild-type controls.
• This delay was associated with reduced Schwann cell proliferation and increased apoptosis in injured nerves.
• Increased fibrin deposits, tPA activity, mature BDNF, and p75 neurotrophin receptor were observed in PN-1 KO sciatic nerves.
• Overexpression of PN-1 in neurons did not rescue the delayed reinnervation phenotype.

Conclusions:

• Schwann cell-derived PN-1 is essential for timely synapse reinnervation and functional recovery after nerve injury.
• PN-1 regulates Schwann cell proliferation and survival, impacting nerve regeneration kinetics.
• Maintaining a balance between proteases and serpins like PN-1 is critical for nerve repair.