A groundbreaking study from Northwestern Medicine, published in Nature Communications, reveals the vital role of aerobic glycolysis in mammalian eye development. While the use of lactate by retinal cells during cell differentiation was known, its significance in early eye development remained a mystery.
Led by Guillermo Oliver, Ph.D., the researchers focused on understanding the molecular and cellular processes governing early eye morphogenesis. They utilized embryonic stem cell-derived eye organoids, artificial tissues grown in the lab. Astonishingly, they observed heightened glycolytic activity and lactate production in early mouse eye progenitors.
To investigate further, the team introduced a glycolysis inhibitor to the cultured organoids, which resulted in the halt of normal optic vesicle development. However, when they reintroduced lactate, the organoids resumed normal eye morphogenesis.
Genome-wide transcriptome and epigenetic analysis further validated the findings. Inhibiting glycolysis and adding lactate to the organoids controlled the expression of critical genes essential for early eye development.
To strengthen their results, the researchers deleted two genes, Glut1 and Ldha, responsible for regulating glucose transport and lactate production in mouse embryos. This deletion specifically disrupted glucose transport in the region responsible for eye formation.
The study's major discovery was the ATP-independent role of the glycolytic pathway. Lactate, previously considered a waste product, emerged as a crucial player in eye morphogenesis. This finding has broad implications, suggesting lactate's involvement in organ development, regeneration, and disease processes.
Moving forward, the researchers plan to leverage traditional and emerging tools in developmental biology, such as mouse genetics and stem cell-derived organoids, to investigate glycolytic pathway and metabolism roles in the development of other organs.
The implications of this research could extend to understanding the impact of metabolites on gene expression during organ regeneration and tumor development. This newfound knowledge of metabolites' influence on gene regulation could potentially lead to novel therapeutic approaches for developmental defects and tumorigenesis.
Source: Northwestern University