Metabolic regulation of species-specific developmental rates

Animals display substantial inter-species variation in the rate of embryonic development despite a broad conservation of the overall sequence of developmental events. Differences in biochemical reaction rates, including the rates of protein production and degradation, are thought to be responsible for species-specific rates of development(1-3). However, the cause of differential biochemical reaction rates between species remains unknown. Here, using pluripotent stem cells, we have established an in vitro system that recapitulates the twofold difference in developmental rate between mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we show that mass-specific metabolic rates scale with the developmental rate and are therefore higher in mouse cells than in human cells. Reducing these metabolic rates by inhibiting the electron transport chain slowed down the segmentation clock by impairing the cellular NAD(+)/NADH redox balance and, further downstream, lowering the global rate of protein synthesis. Conversely, increasing the NAD(+)/NADH ratio in human cells by overexpression of the Lactobacillus brevis NADH oxidase LbNOX increased the translation rate and accelerated the segmentation clock. These findings represent a starting point for the manipulation of developmental rate, with multiple translational applications including accelerating the differentiation of human pluripotent stem cells for disease modelling and cell-based therapies.

Automated summary

Animals display inter-species variation in embryonic development rates, with differences in biochemical reaction rates being thought responsible for species-specific rates. This study establishes an in vitro system using pluripotent stem cells to simulate the twofold difference in developmental rates between mouse and human embryos. The mass-specific metabolic rates were found to scale with developmental rate, higher in mouse cells than in human cells. Manipulating metabolic rates could control developmental rate and have translational applications.