MSGID: 1:317/3 64b220e4   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Understanding metabolites underlying eye development    
    Findings further understanding of the metabolic pathways underlying organ   
   development    
      
     Date:   
         July 14, 2023   
     Source:   
         Northwestern University   
     Summary:   
         Aerobic glycolysis, the process by which cells transform glucose   
         into lactate, is key for eye development in mammals, according to   
         a new study.   
      
      
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   Aerobic glycolysis, the process by which cells transform glucose into   
   lactate, is key for eye development in mammals, according to a new   
   Northwestern Medicine study published inNature Communications.   
      
   While it has been well known that retinal cells use lactate during cell   
   differentiation, the exact role that this process plays in early eye   
   development was not previously understood.   
      
   The findings further the field's understanding of the metabolic pathways   
   underlying organ development, according to Guillermo Oliver, PhD, the   
   Thomas D.   
      
   Spies Professor of Lymphatic Metabolism, Director of the Feinberg   
   Cardiovascular and Renal Research Institute Center for Vascular and   
   Developmental Biology, and senior author of the study.   
      
   "For a long time, my lab has been interested in developmental biology. In   
   particular, to characterize the molecular and cellular steps regulating   
   early eye morphogenesis," Oliver said. "For us, the question was:   
   'How do these remarkable and critical sensory organs we have in our   
   face start to form?'"  Nozomu Takata, PhD, a postdoctoral fellow in   
   the Oliver lab and first author of the paper, initially approached   
   this question by developing embryonic stem cell-derived eye organoids,   
   which are organ-like tissues engineered in a petri dish. Intriguingly,   
   he observed that early mouse eye progenitors display elevated glycolytic   
   activity and production of lactate. After introducing a glycolysis   
   inhibitor to the cultured organoids, normal optic vesicle development   
   halted, according to the study, but adding back lactate allowed the   
   organoids to resume normal eye morphogenesis, or development.   
      
   Takata and his collaborators then compared those organoids to controls   
   using genome-wide transcriptome and epigenetic analysis using RNA   
   and ChIP sequencing. They found that inhibiting glycolysis and adding   
   lactate to the organoids regulated the expression of certain critical   
   and evolutionary conserved genes required for early eye development.   
      
   To validate these findings, Takata deleted Glut1 and Ldha, genes known   
   for regulating glucose transport and lactate production from developing   
   retinas in mouse embryos. The deletion of these genes arrested normal   
   glucose transport specifically in the eye-forming region, according to   
   the study.   
      
   "What we found was an ATP-independent role of the glycolytic pathway,"   
   Takata said. "Lactate, which is a metabolite known as a waste product   
   before, is really doing something cool in eye morphogenesis. That really   
   tells us that this metabolite is a key player in organ morphogenesis   
   and in particular, eye morphogenesis. I see this discovery as having   
   broader implications, as likely also being required in other organs and   
   maybe in regeneration and disease as well."  Following this discovery,   
   Takata said he plans to continue to take advantage of traditional and   
   emerging developmental biology's tools such as mouse genetics and stem   
   cells-derived organoids to study the role of the glycolytic pathway and   
   metabolism in the development of other organs.   
      
   The findings could also be useful in better understanding the direct   
   effect that metabolites could have in regulating gene expression during   
   organ regeneration and tumor development, Oliver said.   
      
   "Both regeneration and tumorigenesis involve developmental pathways   
   that go awry in some occasions, or you need to reactivate," Oliver   
   said. "For many developmental processes, you need very strict   
   transcriptional regulation. A gene is on or off at certain times,   
   and when that goes wrong, that could lead to developmental defects   
   or promote tumorigenesis. Now that we know that there are specific   
   metabolites responsible for normal or abnormal gene regulation, this   
   can broaden our thinking on approaches to therapeutic treatments."   
   Additional Feinberg faculty co-authors include Ali Shilatifard, PhD,   
   the Robert Francis Furchgott Professor and chair of Biochemistry   
   and Molecular Genetics and director of the Simpson Querrey Institute   
   for Epigenetics, Alexander Misharin, MD, PhD, associate professor of   
   Medicine in the Division of Pulmonary and Critical Care, Jason M. Miska,   
   PhD, assistant professor of Neurological Surgery and Navdeep Chandel,   
   PhD, the David W. Cugell, MD, Professor of Medicine in the Division of   
   Pulmonary and Critical Care and of Biochemistry and Molecular Genetics.   
      
   The study was supported by an Illumina Next Generation Sequencing award   
       * RELATED_TOPICS   
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       * RELATED_TERMS   
             o Aerobic_exercise o Blood_sugar o Lactic_acid o Neurobiology   
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   Materials provided by Northwestern_University. Original written by Olivia   
   Dimmer. Note: Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Nozomu Takata, Jason M. Miska, Marc A. Morgan, Priyam Patel, Leah K.   
      
         Billingham, Neha Joshi, Matthew J. Schipma, Zachary J. Dumar,   
         Nikita R.   
      
         Joshi, Alexander V. Misharin, Ryan B. Embry, Luciano Fiore, Peng   
         Gao, Lauren P. Diebold, Gregory S. McElroy, Ali Shilatifard,   
         Navdeep S.   
      
         Chandel, Guillermo Oliver. Lactate-dependent transcriptional   
         regulation controls mammalian eye morphogenesis. Nature   
         Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-39672-2   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230714131134.htm   
      
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