Metabolic Regulation of Species-Specific Developmental Rates

Abstract

Animals display significant inter-species variation in the rate of embryonic development despite broad conservation of the overall sequence of developmental events. Differences in biochemical reaction speeds, 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 speeds between species remains unknown. Using pluripotent stem cells, we have established an in vitro system that recapitulates the two-fold 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 showed that mass-specific metabolic rates scale with developmental rate and are therefore elevated in mouse cells compared to human cells. We further showed that 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 NADH oxidase LbNOX increased translation rate and accelerated the segmentation clock. These findings represent a starting point for the manipulation of developmental rate, with multiple translational applications including the acceleration of human PSCs differentiation for disease modeling and cell-based therapies.