Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway

TLDR

Axon regeneration after CNS injury is limited by both extracellular inhibitors and intrinsic suppression of mTOR signaling, which impairs protein synthesis in retinal ganglion cells and hinders functional recovery. The study aimed to determine whether intrinsic growth‑control genes impede axon regrowth by using a virus‑assisted, in‑vivo conditional knockout strategy. The authors employed a virus‑assisted, in‑vivo conditional knockout approach to delete growth‑regulating genes in adult retinal ganglion cells. Conditional knockout of PTEN or TSC1 reactivates mTOR signaling and drives robust axon regeneration after optic nerve injury, indicating that targeting intrinsic growth‑control pathways is a promising therapeutic strategy.

Abstract

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.