Glucose signaling and embryonic development

Developing zebrafish embryos in which the cells are labelled with a fluorescent marker. The cells in the embryos with impaired MondoA function (bottom) cannot complete the movements seen in the normal embryo (top). Image credit: Weger et al. (CC BY 4.0)

Research by the Dickmeis group published in eLife (https://elifesciences.org/articles/57068) reveals a novel role for the glucose-sensing transcription factor MondoA in early embryonic development. In embryos lacking MondoA function, gene expression in the cholesterol/steroid biosynthesis pathway is perturbed. This perturbation disrupts microtubule cytoskeleton structure in the embryonic yolk, which are essential for development to proceed. The study contributes to our understanding of metabolic information processing in embryonic development. In addition, it suggests MondoA as a potential new target for interfering with cholesterol metabolism in metabolic disease.

Glucose is one of the essential fuels of life. In addition to being degraded to obtain energy, it can also signal to cells that nutrients are available. One cell factor capable of glucose sensing is the protein MondoA. When activated by glucose, MondoA can regulate the transcription of genes in response. Up to now, MondoA function mainly has been studied in the context of adult mammals, revealing for example a role in the regulation of muscle metabolism.
 
Recent studies indicate that specific metabolites and metabolic activities also contribute to the regulation of embryonic development. However, potential functions of the metabolic sensor MondoA during embryonic development of vertebrates had not been addressed so far. Therefore, we examined MondoA function in a small freshwater fish, the zebrafish, which is a popular model organism for vertebrate embryonic development studied in laboratories worldwide.

We reveal that MondoA function is important for the early embryonic development of the zebrafish. When we inhibited the production of MondoA protein in the early embryo, development was blocked due to defective yolk microtubules, protein tubes which serve as structural elements in the cell. We linked this defect to aberrant cholesterol/steroid biosynthesis pathway function. When embryos lacking MondoA function were treated with pregnenolone, a downstream product of this pathway, their microtubule structures were improved and development partially proceeded. Overall, our results uncover a previously unknown role of the glucose-sensing MondoA factor in vertebrate development. 

Genetic mutations in the cholesterol/steroid biosynthesis pathway lead to developmental defects also in humans. By showing that genes in this pathway are under regulation by a cellular glucose sensor, we provide new insights into the metabolic regulation of developmental processes. Furthermore, the link between glucose and cholesterol biogenesis via MondoA mediated regulation of gene transcription suggests examining this factor as a potential new target for drugs interfering with cholesterol metabolism.