Receptors of intermediates of carbohydrate metabolism, GPR91 and GPR99, mediate axon growth.

Abstract

Purpose : During the development of the neurovisual system, high levels of energy are drained to propel axons from the retina to the brain. However, the role of intermediates of carbohydrate metabolism in the development of the neurovisual system has been overlooked.

Methods : Retinal explants were treated with succinate and α-ketoglutarate (agonists of GPR91 and GPR99 respectively) to verify their effects on growth cone morphology and axon growth. Using gpr91, gpr99 and double KO mice, we confirmed that these effects were mediated by these receptors. We assessed the implication of the ERK pathway using Western Blot and CI-1040, an inhibitor of this signaling pathway. The in vivo contribution was established by simultaneous injection of GPR91 and GPR99 ligands and anterograde marker (CTb). Then, we quantified retinal ganglion cell (RGC) projections in the brain. This technique gave us the opportunity to measure the role of these receptors in the development of the retinothalamic pathway.

Results : Here, we report that carbohydrate metabolites succinate and α-ketoglutarate and their respective receptor, GPR91 and GPR99, are involved in modulating RGC projections toward the thalamus during the neurovisual system development. We revealed that GPR91 and GPR99 are expressed on axons of developing RGCs, having complementary roles during RGC axon growth in an ERK_1/2 dependent manner, but no effects on axon guidance.

Conclusions : These findings suggest an important role for these receptors during the establishment of the neurovisual system and provide a link with carbohydrate metabolism in axon growth.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.