Metabolic Plasticity drives Development during Mammalian Embryogenesis

Abstract

SummaryPreimplantation mouse embryos interact minimally with their environment, and development is largely driven by metabolic processes. During the earliest cleavage stages, metabolism is rigid, with maternal deposits enforcing a redox state that facilitates zygotic genome activation. As maternal control falls, metabolic shuttles are activated, increasing glycolysis and equilibrating the TCA cycle. The resulting flexibility of nutrient utilization and metabolic plasticity facilitates unidirectional developmental progression such that later stage embryos proceed to form blastocysts without any exogenously added nutrients. We explore the mechanisms that govern this choreographed sequence that balances the deposition, degradation, synthesis and function of metabolic enzymes with redox control, bioenergetics and biosynthesis. Cancer cells follow a distinct metabolic strategy from that of the preimplantation embryo. However, important shared features emerge under reductive stress. We conclude that metabolic plasticity drives normal development while stress conditions mimic hallmark events in Cancer Metabolism.

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

“…It has been increasingly recognized that the set of external cues driving cell fate decisions includes not only ligands that activate developmental signaling pathways (Perrimon et al, 2012), but also the availability of environmental nutrients (Baksh and Finley, 2021; Lin et al, 2018). Metabolic profiling and systematic identification of metabolic vulnerabilities in different cell types or stages of differentiation across various systems have demonstrated that nutrient availability can not only gate, but also influence, lineage decisions (Gonzalez-Menendez et al, 2021; Oburoglu et al, 2014; Sharpley et al, 2021; Solmonson et al, 2022). While the mechanistic connections between metabolism and cell fate change remain unclear, a few metabolic perturbations have been found to directly alter the levels of metabolites that act as substrates or cofactors for enzymes that control epigenetic marks on chromatin (Baksh and Finley, 2021; Meier, 2013).…”

Oocyte and cumulus cell cooperativity and metabolic plasticity under the direction of oocyte paracrine factors

“…Krisher and Prather [50] have also proposed that oocytes may utilize a metabolic strategy like the Warburg Effect in preparation for rapid embryonic growth after fertilization, whereby glucose is used to generate glycolytic intermediates for ribose-5-phosphate and NADPH production via the pentose phosphate pathway, and lactate is generated from pyruvate to maintain NAD+ levels to support elevated glycolysis. Metabolic plasticity as a driver of mammalian embryogenesis has also recently been reported [51]. We suggest that metabolic plasticity may also be facilitated by OSFs during oocyte maturation, where such oocyte paracrine factors redirect metabolism of some glucose in cumulus cells (e.g.…”

Nutrients in the fate of pluripotent stem cells

“…During this period, glycolytic flux increases as protein synthesis and metabolic shuttles activate (Gardner, 1998;Gardner and Harvey, 2015;Leese and Barton, 1984;Schulz and Harrison, 2019;Zhang et al, 2018a). These changes add flexibility in nutrient dependence because the developing embryo increases enzymes capable of interconverting nutrients (Sharpley et al, 2021). Later stage development, modeled in vitro by PSC-derived tri-lineage germ layer differentiation, loses a requirement for glucose (Chi et al, 2020;Cliff et al, 2017).…”