THESIS
2018
x, 117 pages : illustrations (some color) ; 30 cm
Abstract
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...[
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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.
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