Neuronal mechanistic 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 the peripheral nervous system (PNS) neurons 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 supp...[ Read more ]

Neuronal mechanistic 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 the peripheral nervous system (PNS) neurons 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 effect. In addition, an injury to the peripheral branch boosts mTOR activity in DRG neurons that cannot be completely inhibited by Rapamycin. Unexpectedly, examining several conditioning lesion–induced pro-regenerative pathways revealed that Raptor deletion but not Rapamycin suppressed STAT3 activity in neurons. Furthermore, Pten and TSC1 deletion promoted sensory axon regeneration capacity after spinal cord injury. Behavior analysis revealed that mTORC1 played a dominant role in mediating sensory recovery. 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.