According to a recent Northwestern Medicine study published in Nature Communications, aerobic glycolysis, the process by which cells convert glucose into lactate, is essential for the development of the mammalian eye.
Although lactate is used by retinal cells during cell differentiation, it was not previously known what precise part this process plays in the early stages of eye development.
According to Guillermo Oliver, PhD, the senior author of the study and the Thomas D. Spies Professor of Lymphatic Metabolism, as well as the director of Feinberg Cardiovascular and Renal Research Institute Center for Vascular and Developmental Biology.
My lab has been interested in developmental biology for a very long time. Oliver said,” In particular, to describe the molecular and cellular processes governing early eye morphogenesis.” ” How do these remarkable and important sensory organs we have in our face start to form?” was the question on our minds.
The paper’s first author, Nozomu Takata, PhD, a postdoctoral fellow in the Oliver lab, first approached this issue by creating embryonic stem cell-derived eye organoids, which are organ-like tissues created in petri dishes. He found it intriguing that early mouse eye progenitors exhibit increased lactate production and glycolytic activity. The study found that adding back lactate allowed the cultured organoids to resume normal eye morphogenesis, or development, after a glycolysis inhibitor was added to them.
The organoids were then compared to controls by Takata and his associates using a genome-wide transcriptome and RNA and ChIP sequencing for epigenetic analysis. They discovered that the expression of some crucial and evolutionary conserved genes necessary for early eye development was regulated by inhibiting glycolysis and adding lactate to the organoids.
Takata removed the genes Glut1 and Ldha from developing retinas in mouse embryos to confirm these findings. These genes are responsible for controlling glucose transport and lactate production. According to the study, the deletion of these genes prevented normal glucose transport, particularly in the area that forms the eyes.
Takata stated,” What we discovered was an ATP-independent role of the glycolytic pathway.” The metabolite lactate, which was previously referred to as a waste product, is actually doing something cool in the morphogenesis of the eyes. That clearly demonstrates that this metabolite plays a significant role in the morphogenesis of organs, particularly the eyes. This discovery, in my opinion, has broader ramifications and is probably also necessary for other organs, as well as possibly for regeneration and disease.
Following this discovery, Takata stated that he intends to continue using tools from traditional and cutting-edge developmental biology, such as mouse genetics and stem cell-derived organoids, to investigate the function of the glycolytic pathway and metabolism in the growth of other organs.
According to Oliver, the results may also help us better understand the direct role that metabolites may play in controlling gene expression during organ regeneration and tumor development.
According to Oliver,” both regeneration and tumorigenesis involve developmental pathways that occasionally go awry, or you need to reactivate.” ” You need very strict transcriptional regulation for many developmental processes.” When a gene is on or off at certain times, something could go wrong and cause developmental defects or encourage tumorigenesis. Our understanding of the specific metabolites responsible for normal or abnormal gene regulation can be expanded now that we are aware of these factors. Ali Shilatifard, PhD, the Robert Francis Furchgott Professor, chair of Biochemistry and Molecular Genetics, and director of the Simpson Querrey Institute for Epigenetics are additional faculty members who co-authored this work at Feinberg. Alexander Misharin, Ph.D., is an associate professor of medicine in the Division of Pulmonary and Critical Care. Jason M. Miska is a PhD assistant professor in Neurological Surgery. Navdeep Chandel is the PhD candidate. David W. Cugell
An Illumina Next Generation Sequencing award provided funding for the study.