2. Academic Validation
  3. Lactate-dependent transcriptional regulation controls mammalian eye morphogenesis

Lactate-dependent transcriptional regulation controls mammalian eye morphogenesis

  • Nat Commun. 2023 Jul 14;14(1):4129. doi: 10.1038/s41467-023-39672-2.
Nozomu Takata 1 2,  Jason M Miska # 3 4,  Marc A Morgan # 5 6,  Priyam Patel 7,  Leah K Billingham 3,  Neha Joshi 7,  Matthew J Schipma 7,  Zachary J Dumar 5,  Nikita R Joshi 8,  Alexander V Misharin 8,  Ryan B Embry 7,  Luciano Fiore 1 9,  Peng Gao 10,  Lauren P Diebold 8,  Gregory S McElroy 8 11,  Ali Shilatifard 5,  Navdeep S Chandel 8 12,  Guillermo Oliver 13
Affiliations

Affiliations

  • 1 Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 2 Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA.
  • 3 Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 4 Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 5 Simpson Querrey Institute for Epigenetics and Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 6 Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 7 Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 8 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 9 Laboratory of Nanomedicine, National Atomic Energy Commission (CNEA), Av. General Paz 1499, B1650KNA, San Martín, Buenos Aires, Argentina.
  • 10 Robert H. Lurie Cancer Center Metabolomics Core, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 11 Department of Ophthalmology, Duke University School of Medicine, Durham, NC, 27710, USA.
  • 12 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 13 Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. guillermo.oliver@northwestern.edu.
  • # Contributed equally.
PMID: 37452018 DOI: 10.1038/s41467-023-39672-2
Abstract

Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate Dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.

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