The Warburg Effect and lactate signaling augment Fgf signaling to promote sensory-neural development in the otic vesicle

ABSTRACT Recent studies indicate that many developing tissues modify glycolysis to favor lactate synthesis, but how this promotes development is unclear. Using forward and reverse genetics in zebrafish, we show that disrupting the glycolytic gene phosphoglycerate kinase-1 ( pgk1 ) impairs Fgf-dependent development of hair cells and neurons in the otic vesicle and other neurons in the CNS/PNS. Focusing on the otic vesicle, we found that Fgf signaling underperforms in pgk1 -/- mutants even when Fgf is transiently overexpressed. Wild-type embryos treated with drugs that block synthesis or secretion of lactate mimic the pgk1 -/- phenotype, whereas pgk1 -/- mutants are rescued by treatment with exogenous lactate. Lactate treatment of wild-type embryos elevates expression of Etv5b/Erm even when Fgf signaling is blocked. Thus, by raising steady-state levels of Etv5b (a critical effector of the Fgf pathway), lactate renders cells more responsive to dynamic changes in Fgf signaling required by many developing tissues.