Abstract
During the development of the visual system, high levels of energy are expended propelling axons from the retina to the brain. However, the role of intermediates of carbohydrate metabolism in the development of the visual system has been overlooked. Here, we report that the carbohydrate metabolites succinate and α-ketoglutarate (α-KG) and their respective receptor—GPR91 and GPR99—are involved in modulating retinal ganglion cell (RGC) projections toward the thalamus during visual system development. Using ex vivo and in vivo approaches, combined with pharmacological and genetic analyses, we revealed that GPR91 and GPR99 are expressed on axons of developing RGCs and have complementary roles during RGC axon growth in an extracellular signal–regulated kinases 1 and 2 (ERK1/2)-dependent manner. However, they have no effects on axon guidance. These findings suggest an important role for these receptors during the establishment of the visual system and provide a foundational link between carbohydrate metabolism and axon growth.
Highlights
GPR91 and GPR99 are G-protein-coupled receptors (GPCRs) activated by Krebs cycle intermediates, part of the larger class of carbohydrate metabolites—an observation that renewed interest in a biochemical pathway discovered decades ago [1,2]
We hypothesized that activation of two G-protein-coupled receptors (GPCRs) by metabolic intermediates could promote growth during retinal ganglion cell (RGC) axon extension and guidance from the retina to the brain
We first demonstrated that receptors for two intermediates of carbohydrate metabolism—succinate and α-ketoglutarate—are expressed on developing RGCs and their projections
Summary
GPR91 and GPR99 are G-protein-coupled receptors (GPCRs) activated by Krebs cycle intermediates, part of the larger class of carbohydrate metabolites—an observation that renewed interest in a biochemical pathway discovered decades ago [1,2]. GPR91, through its activation by succinate outside the tricarboxylic acid (TCA) cycle, has a wide range of functions in diverse diseases, such as hypertension and diabetes. Its study allowed greater understanding of the molecular links between the TCA cycle and metabolic diseases [2,3]. The development of the visual system requires high levels of energy to propel mitochondrial-enriched axons properly through the nervous system, as retinal ganglion cells (RGCs) are essential for transmitting information from the retina to the brain. The GC contains multiple receptors that interact with guidance molecules, allowing the front end of a developing axon to navigate through the complex landscape of the early nervous system toward its appropriate targets [7]. The role of intermediates from carbohydrate metabolism during the development of the visual system has not been well characterized
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