Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause

Abstract

Metabolism is crucial for development through supporting cell growth, energy production, establishing cell identity, developmental signaling and pattern formation. In many model systems, development occurs alongside metabolic transitions as cells differentiate and specialize in metabolism that supports new functions. Some cells exhibit metabolic flexibility to circumvent mutations or aberrant signaling, whereas other cell types require specific nutrients for developmental progress. Metabolic gradients and protein modifications enable pattern formation and cell communication. On an organism level, inadequate nutrients or stress can limit germ cell maturation, implantation and maturity through diapause, which slows metabolic activities until embryonic activation under improved environmental conditions.

Keywords: Diapause; Embryogenesis; Metabolism; Signaling.

Fig. 1.

Metabolic activities are specific to developmental stage and cell type. Specific nutrients are required at distinct periods of development both pre- and post-implantation. During pre-implantation, pyruvate, lactate and glucose are required at one- to eight-cell stages (1, 2, 4 and 8) for development to progress. During midgestation, metabolites form gradients that facilitate axis elongation, and disparate fuels are used by developing organs as mitochondrial metabolism increases. The de novo serine biosynthesis pathway is required in the CNS for proper neuron development and function, and for survival of endothelial cells; however, chondrocytes can exhibit metabolic flexibility and either take up or synthesize serine. Created with BioRender.com.

Fig. 2.

Metabolism supports rapid cell growth. Proliferating cells alter metabolic activities, such as increased glycolysis, to support biosynthetic demands, such as nucleotide and lipid synthesis, or energy demands, such as transcription and translation. Lactate production resulting from increased glycolysis can be used as an alternative fuel source by neighboring cells, can form metabolic gradients that alter cell motility and embryonic patterning, or can be excreted to maintain NAD⁺ production by LDH for increased glycolytic flux. Mitochondria can support energy production or export metabolic intermediates to support anabolic pathways through the production of metabolites such as aspartate and citrate (cataplerosis), which must be balanced by nutrient import (e.g. glutamine) into mitochondria (anaplerosis). F1,6BP, fructose 1,6, bisphosphate; G3P, glyceraldehyde 3-phoshate; G6P, glucose 6-phosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LDH, lactate dehydrogenase. Created with BioRender.com.

Fig. 3.

Metabolic mechanisms support developmental signaling. Metabolites can facilitate processes in embryogenesis outside energy and biosynthesis. (A) Polar metabolites can form morphogen gradients that alter cell migration activity and embryonic patterning. (B) Protein signaling ligands can be modified by lipids to restrict long-range signaling or to enhance binding of chaperones that increase long-range signaling. (C) Increased levels of succinate or fumarate can inhibit the activity of prolyl hydroxylases (PHDs), which leads to stabilization of HIF1α (even if oxygen is present) and altered gene transcription. Created with BioRender.com.