Regulation of peripheral nerve regeneration by the mtor pathway.

摘要

While neurons in the central nervous system (CNS) have limited capacity for regrowth after damage, neurons in the peripheral nervous system (PNS) have a robust ability to regenerate their axons following injury. Successful regeneration depends upon both extrinsic cues in the environment and the activation of intrinsic mechanisms to promote regrowth. A number of inhibitory molecules in the CNS environment that prevent axonal regrowth have been identified, but less is known regarding the signaling mechanisms that regulate regenerative ability in PNS neurons. Here, we explored multiple components of injury signaling in the PNS, including the retrograde transport of local axonal injury signals, enhancement of axonal growth capacity in the cell body, and the response of Schwann cells that myelinate the damaged axon.We first addressed how axonal injury triggers enhancement of axonal growth capacity in PNS neurons. The lack of regenerative ability of CNS neurons has been linked to downregulation of the mammalian target of rapamycin (mTOR) pathway. We find that PNS dorsal root ganglia neurons (DRGs) activate mTOR following damage, and that this activity contributes to enhance axonal growth capacity following injury. Furthermore, upregulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We identified GAP-43 as a downstream target of this pathway, which may contribute to enhance regenerative ability. However, while genetic upregulation of mTOR activity in sensory neurons facilitates axonal regrowth, it also leads to a number of developmental and functional defects, including aberrant target innervation. Thus, while manipulation of the mTOR activity could stimulate nerve regeneration in the PNS, fine control of mTOR activity may be required for proper target innervation and functional recovery.mTOR activation in the damaged neuron is likely to represent one of several signaling events that mediate nerve regeneration. We thus also explored other aspects of peripheral nerve injury signaling, including the retrograde transport of local injury signals by axonal vesicles, and the response of myelinating Schwann cells to axonal damage. Our results indicate that several classes of signaling pathways occurring both in axons and Schwann cells cooperate to generate a robust regenerative response. A better understanding of the signaling pathways leading to increased regenerative growth ability of PNS neurons may guide new strategies to enhance nerve regeneration in the CNS.