1. Cytoglobin deficiency potentiates Crb1-mediated retinal degeneration in rd8 mice
- Author
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Kwon, Young Sam, Tham, Addy, Lopez, Antonio Jacobo, Edwards, Sydney, Woods, Sean, Chen, Jiajia, Wong-Fortunato, Jenna, Quiroz Alonso, Alejandra, Javier, Seanne, Au, Ingrid, Clarke, Maria, Humpal, Devin, Lloyd, KC Kent, Thomasy, Sara, Murphy, Christopher, Glaser, Thomas M, and Moshiri, Ala
- Subjects
Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Genetics ,Eye Disease and Disorders of Vision ,Neurosciences ,Rare Diseases ,Neurodegenerative ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Eye ,Animals ,Cytoglobin ,Disease Models ,Animal ,Eye Proteins ,Female ,Homozygote ,Male ,Membrane Proteins ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mutation ,Nerve Tissue Proteins ,Phenotype ,Retina ,Retinal Degeneration ,Retinal Ganglion Cells ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
PurposeThe purpose of this study is to determine the effect of Cytoglobin (Cygb) deficiency on Crb1-related retinopathy. The Crb1 cell polarity complex is required for photoreceptor function and survival. Crb1-related retinopathies encompass a broad range of phenotypes which are not completely explained by the variability of Crb1 mutations. Genes thought to modify Crb1 function are therefore important targets of research. The biological function of Cygb involves oxygen delivery, scavenging of reactive oxygen species, and nitric oxide metabolism. However, the relationship of Cygb to diseases involving the Crb1 cell polarity complex is unknown.MethodsCygb knockout mice homozygous for the rd8 mutation (Cygb-/-rd8/rd8) were screened for ocular abnormalities and imaged using optical coherence tomography and fundus photography. Electroretinography was performed, as was histology and immunohistochemistry. Quantitative PCR was used to determine the effect of Cygb deficiency on transcription of Crb1 related cell polarity genes.ResultsCygb-/-rd8/rd8 mice develop an abnormal retina with severe lamination abnormalities. The retina undergoes progressive degeneration with the ventral retina more severely affected than the dorsal retina. Cygb expression is in neurons of the retinal ganglion cell layer and inner nuclear layer. Immunohistochemical studies suggest that cell death predominates in the photoreceptors. Electroretinography amplitudes show reduced a- and b-waves, consistent with photoreceptor disease. Cygb deficient retinas had only modest transcriptional perturbations of Crb1-related cell polarity genes. Cygb-/- mice without the rd8 mutation did not exhibit obvious retinal abnormalities.ConclusionsCygb is necessary for retinal lamination, maintenance of cell polarity, and photoreceptor survival in rd8 mice. These results are consistent with Cygb as a disease modifying gene in Crb1-related retinopathy. Further studies are necessary to investigate the role of Cygb in the human retina.
- Published
- 2020