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other·retina, ophthalmology, preclinical research, biomedical research·PMC10847449

E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration

Scientific Reports · 19 authors, 6 centres

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TL;DR

Herc3 was identified through a fundus spot accumulation screen in ENU-mutagenized mice and independently validated using two separate CRISPR-generated Herc3 knockout lines on a B6J background.

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Herc3 was identified through a fundus spot accumulation screen in ENU-mutagenized mice and independently validated using two separate CRISPR-generated Herc3 knockout lines on a B6J background. Herc3-deficient mice showed progressive outer retinal thinning on OCT, accumulation of yellow fundus spots, and significantly reduced visual function as measured by optomotor spatial frequency thresholds and ERG. Bulk RNAseq demonstrated upregulation of IL-12 and IL-4 signaling, downregulation of IL-10 signaling, and differential expression of genes involved in microglial activation modulation. Some evidence suggested greater retinal thinning and fundus spot accumulation in female mice, though the study was not powered to fully assess sex effects.

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other

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retina

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ORIGINAL PAPER

PMC10847449

E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration

Scientific Reports

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ABSTRACT

Abstract Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of identifying novel genes associated with microglial activation in the retina, we applied a semiquantitative fundus spot scoring scale to an unbiased, state-of-the-science mouse forward genetics pipeline. A mutation in the gene encoding the E3 ubiquitin ligase Herc3 led to prominent accumulation of fundus spots. CRISPR mutagenesis was used to generate Herc3 -/- mice, which developed prominent accumulation of fundus spots and corresponding activated Iba1 + /CD16 + subretinal microglia, retinal thinning on OCT and histology, and functional deficits by Optomotory and electrophysiology. Bulk RNA sequencing identified activation of inflammatory pathways and differentially expressed genes involved in the modulation of microglial activation. Thus, despite the known expression of multiple E3 ubiquitin ligases in the retina, we identified a non-redundant role for Herc3 in retinal homeostasis. Our findings are significant given that a dysregulated ubiquitin–proteasome system (UPS) is important in prevalent retinal diseases, in which activated microglia appear to play a role. This association between Herc3 deficiency, retinal microglial activation and retinal degeneration merits further study. Keywords: Herc3, Forward genetics, ENU-mutagenesis, CRISPR, Retinal neurodegeneration, Fundus spots, Screening, Phenotype-genotype association, Microglia Subject terms: Retinal diseases, Transcriptomics, Animal disease models

CITATION EXPORT

Yeshumenesh Zegeye, Bogale Aredo, Seher Yuksel et al.. E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration. Scientific Reports. (2024). https://doi.org/10.1038/s41598-024-53731-8

AUTHORS

19 · 6 CENTRES

Yeshumenesh Zegeye, Bogale Aredo, Seher Yuksel, Dogan Can Kirman, Ashwani Kumar, Bo Chen, Emily Turpin, Sangita Shresta, Yu-Guang He, Laurent Gautron, Miao Tang, Xiaohong Li, Sophia M DiCesare, John D Hulleman, Chao Xing, Sara Ludwig, Eva Marie Y Moresco, Bruce A Beutler, Rafael L Ufret-Vincenty

1Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX USA
2McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX USA
3Center for Hypothalamic Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
4Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX USA
5Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX USA
6Present Address: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China