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Enhancing intrinsic growth capacity promotes adult CNS regeneration
1Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China. cp_yang_1999@yahoo.com
Abstract:
In the adult mammalian central nervous system (CNS), the axons do not spontaneously regenerate after injury due to the inhibitory extrinsic environment and a diminished intrinsic regenerative capability. Many previous studies focus largely on characterizing the hostile growth inhibitory molecules in the CNS. In fact, blocking such inhibitory activities by either genetic or pharmacological approaches only allows limited sprouting, and majority of the adult neurons fail to regenerate their axons even provided with permissive substrates. Upon the neural circuits established during development, the intrinsic neuronal growth activity is gradually repressed. Little is known to the mechanisms for transition from the robust growth mode of the immature neurons to the poor growth mode of the mature neurons and the way to reactivate the intrinsic growth capacity after injury. The primary sensory neurons with cell bodies in the dorsal root ganglion (DRG) provide a useful model to develop strategies to enhance the intrinsic growth capacity of neurons. The centrally projecting axons in the adult spinal cord do not regenerate, while the peripheral branches regenerate robustly after injury. Regeneration of the central branches can be significantly enhanced after a prior peripheral branch injury, which is defined as conditioning lesion. We reviewed the mode of conditioning lesion reactivating the intrinsic growth program. Importantly, we summarized the intrinsic neuronal determinants for neurite growth such as cAMP, PTEN/mTOR, APC-Cdh1, KLF4, etc., the mechanisms underlying development-dependent decline of CNS neurons growth ability, and procedures to enhance the intrinsic growth potential.
Insights
Axon regeneration in adult mammals is limited by inhibitory environments and reduced intrinsic growth capacity. Conditioning lesions can reactivate intrinsic neuronal growth programs, offering strategies to enhance axon repair after central nervous system injury.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Cell Biology
Background:
- Adult mammalian central nervous system (CNS) axons fail to regenerate after injury due to inhibitory environments and decreased intrinsic growth capacity.
- While blocking inhibitory molecules yields limited sprouting, understanding and reactivating intrinsic neuronal growth potential is crucial for effective axon regeneration.
- Dorsal root ganglion (DRG) neurons serve as a model, exhibiting differential regeneration of peripheral versus central axons and enhanced central regeneration after conditioning lesions.
Purpose of the Study:
- To review mechanisms by which conditioning lesions reactivate intrinsic neuronal growth programs.
- To summarize intrinsic neuronal determinants of neurite growth, including cAMP, PTEN/mTOR, APC-Cdh1, and KLF4.
- To elucidate the developmental decline in CNS neuron growth ability and explore methods to enhance intrinsic growth potential.
Main Methods:
- Review of existing literature on CNS axon regeneration, conditioning lesions, and intrinsic neuronal growth factors.
- Analysis of molecular mechanisms underlying the transition from immature to mature neuronal growth states.
- Examination of studies investigating strategies to enhance intrinsic neuronal growth capacity.
Main Results:
- Conditioning lesions can significantly enhance the regeneration of central axon branches in DRG neurons.
- Key intrinsic neuronal factors such as cAMP, PTEN/mTOR signaling, APC-Cdh1, and KLF4 play critical roles in neurite outgrowth.
- The intrinsic growth capacity of CNS neurons declines during development, a process influenced by multiple molecular pathways.
Conclusions:
- Reactivating intrinsic neuronal growth programs is essential for promoting CNS axon regeneration after injury.
- Understanding the molecular determinants of neurite growth and developmental decline offers therapeutic targets for enhancing neural repair.
- Strategies focusing on boosting intrinsic neuronal potential, alongside addressing extrinsic inhibitory factors, are promising for CNS regeneration.
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