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| Status |
Public on Apr 19, 2019 |
| Title |
Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain stuied at single-cell resolution |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The mammalian central nervous system (CNS) is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin-knockout (NdpKO) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypovascularization of the retina produces chronic hypoxia of inner nuclear layer (INL) neurons and Muller glia. We have used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13C-glucose to compare wild type 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 tricarboxylic acid 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 to those in the hypoxic cerebral cortex of mice that were housed for one 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 neo-angiogenic 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.
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| Overall design |
Single-cell RNAseq of NdpKO and WT retinas as well as normoxic and hypoxic cerebral cortices; Ribotag RNA-seq of NdpKO and WT retinas; RNA-seq of normoxic and hypoxic whole brains.
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| Contributor(s) |
Heng JS, Rattner A, Stein-O'Brien GL, Winer BL, Jones BW, Vernon HJ, Goff LA, Nathans J |
| Citation(s) |
30988181 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 EY018637 |
The control of retinal vascular development by Norrin and Frizzled4 |
JOHNS HOPKINS UNIVERSITY |
JEREMY NATHANS |
| R01 EY015128 |
Retinal Remodeling |
UNIVERSITY OF UTAH |
Bryan William Jones |
| P30 EY014800 |
University of Utah, Core Vision Research Grant |
UNIVERSITY OF UTAH |
ROBERT E MARC |
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| Submission date |
Jan 27, 2019 |
| Last update date |
Apr 19, 2019 |
| Contact name |
Jacob S Heng |
| E-mail(s) |
jacob.heng@outlook.com
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| Organization name |
Johns Hopkins University School of Medicine
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| Department |
Molecular Biology and Genetics
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| Lab |
Nathans Lab
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| Street address |
725 North Wolfe Street
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21210 |
| Country |
USA |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (23)
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| Relations |
| BioProject |
PRJNA517321 |
| SRA |
SRP182592 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125708_RAW.tar |
113.3 Mb |
(http)(custom) |
TAR (of MTX, TSV, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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