Both the declined intrinsic growth capacity and hostile extrinsic environment contribute to axon regeneration failure in the central nerve system (CNS). Phosphatase and tensin homolog (Pten) and mechanistic target of Rapamycin (mTOR) pathway have been well-documented as a major intrinsic controller of axon regeneration. Pten deletion elevates mTOR activity and induces robust axon regeneration in both injured optic nerves and spinal cords. Chondroitin sulfate proteoglycans (CSPGs) are the major extrinsic inhibitors in lesion scars, which degradation by the enzyme Chondroitinase ABC (ChABC) promotes axon regeneration after spinal cord injury. However, the axon regeneration induced by both mechanisms is partial and far away from functional recovery. It remains inconclusive if targ...[ Read more ]

Both the declined intrinsic growth capacity and hostile extrinsic environment contribute to axon regeneration failure in the central nerve system (CNS). Phosphatase and tensin homolog (Pten) and mechanistic target of Rapamycin (mTOR) pathway have been well-documented as a major intrinsic controller of axon regeneration. Pten deletion elevates mTOR activity and induces robust axon regeneration in both injured optic nerves and spinal cords. Chondroitin sulfate proteoglycans (CSPGs) are the major extrinsic inhibitors in lesion scars, which degradation by the enzyme Chondroitinase ABC (ChABC) promotes axon regeneration after spinal cord injury. However, the axon regeneration induced by both mechanisms is partial and far away from functional recovery. It remains inconclusive if targeting both extrinsic and intrinsic pathways together further promotes axon regeneration. It also remains largely unknown if the extrinsic inhibitors and intrinsic programs affect each other in vivo.

Here I found that degrading CSPGs by ChABC promotes axon regeneration in the injured optic nerve, and for the first time, activates mTORC1 in retinal ganglion cells (RGCs). Similarly, knocking out/down the CSPGs receptors in the RGCs elevates mTORC1 activity. Exaggerating CSPGs and other myelin-related inhibitors like MAG and Nogo-A in the lesion sites directly suppress the mTORC1 activity in RGCs. Moreover, the downregulation of mTORC1 by CSPGs needs retrograde axonal transportation and the ChABC induced axon regeneration is mTOR and neuronal activity-dependent. In addition, Pten or socs3 deletion combined with ChABC treatment promotes further mTOR-dependent axon regeneration. However, ChABC plus Pten Socs3 double deletion failed to boost further axonal regeneration. It may imply a balance between extrinsic and intrinsic pathways in mediating CNS axon regeneration. In sum, I propose the extrinsic inhibitors (CSPGs) suppressing axon regeneration in CNS by down-regulating intrinsic mTOR pathway.