Metabolic regulation of species-specific developmental rates

Margarete Diaz-Cuadros (), Teemu P. Miettinen, Owen S. Skinner, Dylan Sheedy, Carlos Manlio Díaz-García, Svetlana Gapon, Alexis Hubaud, Gary Yellen, Scott R. Manalis, William M. Oldham and Olivier Pourquié ()
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Margarete Diaz-Cuadros: Harvard Medical School
Teemu P. Miettinen: Massachusetts Institute of Technology
Owen S. Skinner: Massachusetts General Hospital
Dylan Sheedy: Harvard Medical School
Carlos Manlio Díaz-García: Harvard Medical School
Svetlana Gapon: Harvard Medical School
Alexis Hubaud: Harvard Medical School
Gary Yellen: Harvard Medical School
Scott R. Manalis: Massachusetts Institute of Technology
William M. Oldham: Harvard Medical School
Olivier Pourquié: Harvard Medical School

Nature, 2023, vol. 613, issue 7944, 550-557

Abstract: Abstract 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 development1–3. 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.

Date: 2023
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DOI: 10.1038/s41586-022-05574-4

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