• Understanding metabolites underlying eye

    From ScienceDaily@1337:3/111 to All on Fri Jul 14 22:30:26 2023
    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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    ==========================================================================
    FULL STORY ========================================================================== 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
    o Health_&_Medicine
    # Eye_Care # Medical_Topics # Stem_Cells # Genes
    o Mind_&_Brain
    # Child_Development # Learning_Disorders #
    Infant_and_Preschool_Learning # Intelligence
    * RELATED_TERMS
    o Aerobic_exercise o Blood_sugar o Lactic_acid o Neurobiology
    o Glycogen o Tooth_development o Glutamic_acid o Eye

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    Materials provided by Northwestern_University. Original written by Olivia Dimmer. Note: Content may be edited for style and length.


    ========================================================================== 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 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2023/07/230714131134.htm

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