Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway
Open accessAbstract
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
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Counting CTB-labeled axons at different distances from the crush site estimates the number of regenerating axons in the optic nerve.
“The number of regenerating axons in the optic nerve was estimated by counting the number of CTB-labeled axons at different distances from the crush site as described previously29.”
From Reprogramming to recover youthful epigenetic information and restore vision (2020) · cites this paper as [29]
Deletion of TSC1 has neuroprotective effects.
“Genetic and pharmacological evidence has shown that deletion of TSC1, a negative regulator of mTOR signaling, led to constitutive activation of mTOR, neuroprotective effects and potently enhanced axon regeneration (Park et al., 2008).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Park et al., 2008
Deletion of TSC1 leads to constitutive activation of mTOR.
“Genetic and pharmacological evidence has shown that deletion of TSC1, a negative regulator of mTOR signaling, led to constitutive activation of mTOR, neuroprotective effects and potently enhanced axon regeneration (Park et al., 2008).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Park et al., 2008
Deletion of TSC1 potently enhances axon regeneration.
“Genetic and pharmacological evidence has shown that deletion of TSC1, a negative regulator of mTOR signaling, led to constitutive activation of mTOR, neuroprotective effects and potently enhanced axon regeneration (Park et al., 2008).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Park et al., 2008
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- Authors
- Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai, B., Xu, B., Connolly, L., Kramvis, I., Sahin, M., & He, Z.
- Affiliations
- Harvard University (US)
- F. M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
- Corresponding author
- Park, Kevin Kyungsuk
- Liu, Kai
- Hu, Yang
- Smith, Patrice D.
- He, Zhigang
- ORCID
- Venue
- Science
- Published
- 2008-11-07
- Volume
- 322
- Issue
- 5903
- Pages
- 963-966
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2652400
- OpenAlex
- W2004538934
- Cited by
- 1,686
- References
- 27
- Citations by year
- 2026: 80 · 2025: 93 · 2024: 92 · 2023: 119 · 2022: 116 · 2021: 99 · 2020: 126 · 2019: 112 · 2018: 112 · 2017: 94 · 2016: 104 · 2015: 85 · 2014: 104 · 2013: 79 · 2012: 97
- FWCI
- 24.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS058956, R01NS051788)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- axon regeneration, PTEN, mTOR signaling, tuberous sclerosis complex 1, retinal ganglion cells, optic nerve injury, central nervous system injury, conditional knockout, protein synthesis
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Animals, Axons, Carrier Proteins, Cell Survival, Nerve Crush, Nerve Regeneration, Optic Nerve, Retinal Ganglion Cells, Protein Biosynthesis, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Axotomy, Tumor Suppressor Proteins, Ribosomal Protein S6, PTEN Phosphohydrolase, Mice, TOR Serine-Threonine Kinases
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