Enhancing intrinsic growth capacity promotes adult CNS regeneration

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.