Roles of mTOR in regulating mammalian central axon regeneration

Abstract

The failure of CNS axon regeneration is the major obstacle for functional recovery after traumatic injury. Exploring the mechanisms to promote axon regeneration is essential for the potential clinical trials. In the first studies, we found that subtypes of ipRGCs in mice maintained high mTOR levels after axotomy and the light-sensitive melanopsin mediated this sustained expression. Melanopsin overexpression in RGCs stimulated axon regeneration after optic nerve crush. Activation of Gq in RGCs elevated mTOR and promoted axon regeneration. Melanopsin overexpression in RGCs enhanced neuronal activity, silencing them with Kir2.1 suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. So enhancement of neuronal activity with optogenetics and chemogenetics methods promotes axon regeneration. In the second studies, we found that the mTOR activation regulates the expression level and localization of lipin1, a key gene controlling the balanced synthesis of phospholipids and triacylglycerol (TAG). Depleting lipin1 in RGCs, axon regeneration significantly enhanced. Lipin1 level increased during development and further upregulated after axotomy in αRGCs, which may contribute to the regeneration failure by favoring TAG production instead of phospholipids. Forced TAG storage blocked the axon regeneration. Conversely, inhibiting DGATs, crucial enzymes catalyzing TAG synthesis, increased phospholipids and also promoted axon regeneration. Furthermore, impairment of phospholipids synthesis suppressed axon regeneration induced by lipin1 depletion while the elevation of phospholipids synthesis promoted axon regeneration. Our study reveals a critical role of Lipin1/DGATs in the neuron and indicates that directing neuronal lipid synthesis from TAG to phospholipids can be targeted for axon regeneration.

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology