Novel roles for osteopontin and clusterin in peripheral motor and sensory axon regeneration

Previous studies demonstrated that Schwann cells (SCs) express distinct motor and sensory phenotypes, which impact the ability of these pathways to selectively support regenerating neurons. In the present study, unbiased microarray analysis was used to examine differential gene expression in denervated motor and sensory pathways in rats. Several genes that were significantly upregulated in either denervated sensory or motor pathways were identified and two secreted factors were selected for further analysis: osteopontin (OPN) and clusterin (CLU) which were upregulated in denervated motor and sensory pathways, respectively. Sciatic nerve transection induced upregulation of OPN and CLU and expression of both returned to baseline levels with ensuing regeneration. In vitro analysis using exogenously applied OPN induced outgrowth of motor but not sensory neurons. CLU, however, induced outgrowth of sensory neurons, but not motor neurons. To assess the functional importance of OPN and CLU, peripheral nerve regeneration was examined in OPN and CLU^-/- mice. When compared with OPN^+/+ mice, motor neuron regeneration was reduced in OPN^-/- mice. Impaired regeneration through OPN^-/- peripheral nerves grafted into OPN^+/+ mice indicated that loss of OPN in SCs was responsible for reduced motor regeneration. Sensory neuron regeneration was impaired in CLU^-/- mice following sciatic nerve crush and impaired regeneration nerve fibers through CLU^-/- nerve grafts transplanted into CLU^+/+ mice indicated that reduced sensory regeneration is likely due to SCderived CLU. Together, these studies suggest unique roles for SC-derived OPN and CLU in regeneration of peripheral motor and sensory axons.