PTEN/SOCS3 Co-Deletion Accelerates Functional Recovery Following Peripheral Nerve Damage

Guerrero, Walter

There are approximately 2 million peripheral nerve injuries as a result of trauma each year. The peripheral nervous system has some capacity for regeneration after injury, but full functional recovery is rare. Recent studies have shown that conditional deletion of the key signaling inhibitors-phosphatase and tensin homolog (PTEN) and suppressor of cytokine signaling-3 (SOCS3)-leads to regeneration of injured axons in the optic nerve and corticospinal tract. Work in the peripheral nervous system indicates that modification of the PI3K pathway may have a positive impact on regeneration; however, PTEN and PTEN/SOCS3 co-deletion within the dorsal root ganglia (DRG)-the location of peripheral sensory neurons-has not been previously investigated. We tested the hypothesis that PTEN and/or PTEN/SOCS3 co-deletion in DRG neurons will enhance the recovery of sensory function in mice following a sciatic nerve crush. We found that deletion of PTEN does not have an effect on recovery following a sciatic nerve crush. PTEN/SOCS3 co-deletion in DRG neurons enhanced the recovery rate of sensory function but had no effect on final outcome. Immunofluorescent staining of DRG sections revealed that PTEN is normally expressed in small diameter neurons while p-S6, a ribosomal protein downstream of PTEN, is expressed in large diameter neurons. Western blot analysis showed that the PI3K and Jak/Stat pathways were activated for a relatively brief period after sciatic nerve crush, both returning to baseline within seven days. Behavioral tasks performed addressed pressure and heat sensation. Behavioral tasks for pressure and heat sensation as well as motor function indicated that PTEN/SOCS3 co-deletion improved the recovery rate of sensory function, although there was no effect on final outcomes. As expected, there was no effect of either deletion paradigm on motor recovery. Although, PTEN/SOCS3 co-deletion had no significant impact on final outcome in mice, an enhanced recovery rate may have a greater impact in human patients where distances from injury site to denervated targets are far greater. The ultimate goal of this work is to guide the therapeutic treatment of nerve damage in order to improve functional recovery for millions of people each year.