The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury

Abstract

The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3 mm beyond the injury site at 8 weeks after injury. Concomitantly, treatment with PF-4708671 produced significant locomotor recovery. Pharmacological targeting of S6K1 may therefore constitute an attractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

“…The data on PTEN loss indicate a pro-regenerative role for PIP3, in keeping with other studies that implicate PI3K in the regulation of axon growth and regeneration (Al-Ali et al, 2017;Cosker and Eickholt, 2007). Importantly, PTEN deletion enhances regeneration through downstream signalling within the cell body (Park et al, 2008), but it is not known whether it also has effects within the axon.…”

“…The class I phospholipids are strongly implicated in the regulation of regenerative ability because transgenic deletion of PTEN, an enzyme which opposes PI3K by converting PIP3 back to PIP2, promotes CNS regeneration (Geoffroy et al, 2015;Liu et al, 2010;Park et al, 2008), whilst inhibition of a negative feedback to this pathway similarly enhances regrowth (Al-Ali et al, 2017). These findings indicate a pro-regenerative role for PIP3, although this molecule has not been directly studied in adult CNS axons.…”

Can injured adult CNS axons regenerate by recapitulating development?

“…Together, these results support a model in which developing neurons signal through mTOR to translate proteins more effectively than adult neurons do, and suggest that enhancing mTOR-mediated protein translation in adulthood can boost axon regeneration. However, it has been reported that S6K1 restricts mouse corticospinal axon regeneration (Al-Ali et al, 2017). These results highlight the complexity of mTOR signalling in regeneration and suggest that more research is needed to understand how different effectors of the PI3K/Akt/ mTOR pathway influence axon growth.…”

Intrinsic mechanisms of neuronal axon regeneration

“…However, both the upstream and downstream mechanisms involved in mTOR function in axon regeneration are not well understood. Crosstalk between mTOR and STAT3 signalling pathways 97 , as well as negative feedback by the mTOR downstream target ribosomal protein S6 kinase-β1 (S6K1) 98 , suggest that a deeper understanding of this master regulator of axon growth is needed.…”