Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution

The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO (NdpKO ) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypo-vascularization of the retina produces c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-04, Vol.116 (18), p.9103-9114
Main Authors: Heng, Jacob S., Rattner, Amir, Stein-O’Brien, Genevieve L., Winer, Briana L., Jones, Bryan W., Vernon, Hilary J., Goff, Loyal A., Nathans, Jeremy
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Brain
Brain - metabolism
Cerebral cortex
Disease Models, Animal
Endothelial cells
Endothelial Cells - metabolism
Exudation
Familial Exudative Vitreoretinopathies - genetics
Familial Exudative Vitreoretinopathies - physiopathology
Familial exudative vitreoretinopathy
Female
Gene expression
Gene sequencing
Glutathione
Glycine
Hypoxia
Hypoxia - metabolism
Male
Metabolomics
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins - metabolism
Neuroglia - metabolism
Neuronal-glial interactions
Neurons
Neurons - metabolism
Oxygen
PNAS Plus
Retina
Retina - metabolism
Retina - physiology
Retinal Neurons - metabolism
Retinal Vessels - metabolism
Ribonucleic acid
RNA
Sequence Analysis, RNA - methods
Serine
Single-Cell Analysis - methods
Tricarboxylic acid cycle
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Summary:The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO (NdpKO ) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypo-vascularization of the retina produces chronic hypoxia of inner nuclear-layer (INL) neurons and Muller glia. We used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13C-glucose to compare WT and NdpKO retinas. In NdpKO retinas, we observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and we find a metabolic shift that combines reduced flux through the TCA cycle with increased synthesis of serine, glycine, and glutathione. We also used single-cell RNA sequencing to compare the responses of individual cell types in NdpKO retinas with those in the hypoxic cerebral cortex of mice that were housed for 1 week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the response of Muller glia in the NdpKO retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression program, which likely underlies the adaptive neoangiogenic response to chronic hypoxia. These analyses of retina and brain transcriptomes at single-cell resolution reveal both shared and cell type-specific changes in gene expression in response to chronic hypoxia, implying both shared and distinct cell type-specific physiologic responses.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1821122116