The Warburg Effect and Lactate Signaling Augment Fgf Signaling to Promote Sensory‐neural Development in the Otic Vesicle

Abstract

In a forward ENU screen in zebrafish, we recovered a novel mutation that specifically impairs development of sensory hair cells and neurons in the otic vesicle. Whole‐genome sequencing identified a null mutation in the gene encoding the glycolytic enzyme Phosphoglycerate Kinase‐1 (Pgk1). Targeted disruption of Pgk1 using CRISPR/Cas9 yields an identical phenotype. Surprisingly, analysis of genetic mosaics showed that Pgk1 acts non‐autonomously to promote efficient Fgf signaling at a distance, as required for specification of neurons and hair cells of the inner ear. Expression of known Fgf ligands appears normal but Fgf‐reporters Pea3 and Erm are dramatically under‐expressed in mutant embryos. Moreover, transient overexpression of Fgf8 from an inducible transgene does not rescue the phenotype, suggesting a problem with signal transduction. These and other data led us to the discovery that otic cells require metabolic reprogramming to enhance glycolysis and “aerobic fermentation” – similar to the “Warburg Effect” exhibited by tumor cells – to promote synthesis and secretion of lactate. Wild‐type embryos treated with drugs that block synthesis or secretion of lactate mimic the phenotype of Pgk1 mutants, whereas Pgk1 mutants are fully rescued by treatment with exogenous lactate. Lactate treatment of wild‐type embryos elevates expression of Pea3 and Erm even when Fgf signaling is blocked. Thus, by raising steady‐state levels of Pea3 and Erm (critical effectors of the Fgf‐MAPK pathway), lactate signaling primes the pathway and renders cells more responsive to dynamic changes in Fgf signaling required for sensory‐neural development in the inner ear.Support or Funding InformationNIH‐NIDCD grant R01‐DC03806This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.