Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions. To establish whether the impact of mTOR on axon regeneration results from functions of mTOR complex 1 (mTORC1) or 2 (mTORC2), two distinct kinase complexes, we ablated either Raptor or Rictor in DRG neurons. We found that suppressing mTORC1 signaling dramatically decreased the conditioning lesion (CL) effect. In addition, an injury to the peripheral branch boosts the mTOR activity in DRG neurons that cannot be completely inhibited by rapamycin, a widely used mTOR-specific inhibitor. Unexpectedly, examining several conditioning lesion induced pro-regenerative pathways revealed that Raptor deletion but not rapamycin suppressed Stat3 activity in neurons. Therefore, our results demonstrate that crosstalk between mTOR and Stat3 signaling mediates the conditioning lesion effect, and provides genetic evidence that rapamycin-resistant mTOR activity contributes to the intrinsic axon growth capacity in adult sensory neurons after injury.
SIGNIFICANCE STATEMENT: Adult CNS axons usually do not regenerate after injury. Understanding mechanisms of axon regeneration in the PNS neurons will help us to develop methods to promote axonal regeneration in the CNS. mTOR is one of the key factors to enhance the regeneration ability of CNS neurons. However, there is no consensus about the effect of mTOR on axon regeneration in the PNS. We provide genetic evidence that mTOR, in particular mTORC1, is required for peripheral lesion-initiated pro-regenerative programs of dorsal root ganglion neurons. Peripheral lesion enhances the rapamycin-insensitive mTOR activity that boosts Stat3 signaling, a transcription factor essential for axon regeneration. Our findings support that injury-induced neuronal mTOR activity in PNS neurons contributes to their intrinsic ability to regenerate axons.