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.
| Original language | English (US) |
|---|---|
| Article number | 4129 |
| Journal | Nature communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Funding
Metabolomics services were provided by the Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The public data deposition is supported by the Metabolomics Workbench/National Metabolomics Data Repository (NMDR) (grant# U2C-DK119886), Common Fund Data Ecosystem (CFDE) (grant# 3OT2OD030544) and Metabolomics Consortium Coordinating Center (M3C) (grant# 1U2C-DK119889). RNA-seq, scRNA-seq and ChIP-seq work were supported by the Northwestern University NUSeq Core Facility. We thank Masayuki Oginuma (Osaka University) and Jun Watanabe (Northwestern University) for technical advice with the glucose tracing experiments and HDAC-mediated epigenetic modification, respectively. Sandra Acosta (University of Barcelona), Beatriz Sosa-Pineda (Northwestern University), Jason S. Shapiro (Northwestern University), Soh Yamamoto (Sapporo Medical University School of Medicine) and Hidenobu Miyazawa (European Molecular Biology Laboratory) for critical comments. For valuable animal resources, we want to thank E. Dale Abel (University of Iowa), Seth Blackshaw (Johns Hopkins University) and Susan E. Quaggin (Northwestern University). Funding: 2020 Illumina pilot project AAA-Next Generation Sequencing award to G.O. Metabolomics services were provided by the Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The public data deposition is supported by the Metabolomics Workbench/National Metabolomics Data Repository (NMDR) (grant# U2C-DK119886), Common Fund Data Ecosystem (CFDE) (grant# 3OT2OD030544) and Metabolomics Consortium Coordinating Center (M3C) (grant# 1U2C-DK119889). RNA-seq, scRNA-seq and ChIP-seq work were supported by the Northwestern University NUSeq Core Facility. We thank Masayuki Oginuma (Osaka University) and Jun Watanabe (Northwestern University) for technical advice with the glucose tracing experiments and HDAC-mediated epigenetic modification, respectively. Sandra Acosta (University of Barcelona), Beatriz Sosa-Pineda (Northwestern University), Jason S. Shapiro (Northwestern University), Soh Yamamoto (Sapporo Medical University School of Medicine) and Hidenobu Miyazawa (European Molecular Biology Laboratory) for critical comments. For valuable animal resources, we want to thank E. Dale Abel (University of Iowa), Seth Blackshaw (Johns Hopkins University) and Susan E. Quaggin (Northwestern University). Funding: 2020 Illumina pilot project AAA-Next Generation Sequencing award to G.O.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy