The Appearance of the Warburg Effect in the Developing Avian Eye Characterized In Ovo: How Neurogenesis Can Remodel Neuroenergetics.

Purpose: The avian eye is an established model for exploring mechanisms that coordinate morphogenesis and metabolism during embryonic development. Less is known, however, about trafficking of bioenergetic and metabolic signaling molecules that are involved in retinal neurogenesis. Methods: Here we tested whether the known 3-day delayed neurogenesis occurring in the pigeon compared with the chick was associated with a deferred reshaping of eye metabolism in vivo. Developmental metabolic remodeling was explored using 1H-magnetic resonance spectroscopy of the whole eye and vitreous body, in ovo, in parallel with biochemical and molecular analyses of retinal, vitreous, and lens extracts from bird embryos. Results: Cross-species comparisons enabled us to show that a major glycolytic switch in the retina is related to neurogenesis rather than to eye growth. We further show that the temporal emergence of an interlocking regulatory cascade controlling retinal oxidative phosphorylation and glycolysis results in the exchange of lactate and citrate between the retina and vitreous. Conclusions: Our results point to the vitreous as a reservoir and buffer of energy metabolites that provides trophic support to oxidative neurons, such as retinal ganglion cells, in early development. Through its control of key glycolytic regulatory enzymes, citrate, exchanged between extracellular and intracellular compartments between the retina and vitreous, is a key metabolite in the initiation of a glycolytic switch.