Cytoglobin deficiency potentiates Crb1-mediated retinal degeneration in rd8 mice

Tham, Addy; Lopez, Antonio Jacobo; Edwards, Sydney; Woods, Sean; Chen, Jiajia; Wong-Fortunato, Jenna; Alonso, Alejandra Quiroz; Javier, Seanne; Au, Ingrid; Clarke, Maria; Humpal, Devin; Lloyd, Kevin C K; Thomasy, Sara M; Murphy, Christopher J.; Gläser, Thomas; Moshiri, Ala

doi:10.1016/j.ydbio.2019.10.013

Cited by 10 publications

(9 citation statements)

References 58 publications

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“…Using this model, they demonstrated for the first time that following induction of membrane damage and oxidative stress in the liver using thioacetamide, TG mice were better withstanding the increase in ROS and inflammation, displaying reduced neutrophil accumulation and release of inflammation-related cytokines, less hepatic fibrosis with decreased activation of hepatic stellate cells compared to wild-type mice [ 282 ]. Kwon et al very recently showed that Cygb -deficiency affects retinal degeneration in mice with defects in the expression of Crumbs1, caused by a point mutation in the rd8 gene [ 283 ]. Indeed, Cygb -/-rd8/rd8 mice displayed a more rapid degeneration of the retina than Cygb +/+rd8/rd8 mice, with a more marked photoreceptor degeneration and defective lamination of progenitor cells, Muller glia and new photoreceptors.…”

Section: Cytoglobinmentioning

confidence: 99%

“…Indeed, Cygb -/-rd8/rd8 mice displayed a more rapid degeneration of the retina than Cygb +/+rd8/rd8 mice, with a more marked photoreceptor degeneration and defective lamination of progenitor cells, Muller glia and new photoreceptors. Kwon and colleagues suggested a ROS scavenging-related role for Cygb for the regulation of the polarity of photoreceptor and progenitor cells in the retina [ 283 ]. Most recently, additional evidence for the antioxidative function of Cygb in the kidney was demonstrated by using a Cygb -deficient murine model, displaying reduced kidney function and podocyte number [ 284 ].…”

Section: Cytoglobinmentioning

confidence: 99%

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Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

et al. 2020

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Vertebrate hemoglobin (Hb) and myoglobin (Mb) were among the first proteins whose structures and sequences were determined over 50 years ago. In the subsequent pregenomic period, numerous related proteins came to light in plants, invertebrates and bacteria, that shared the myoglobin fold, a signature sequence motif characteristic of a 3-on-3 α-helical sandwich. Concomitantly, eukaryote and bacterial globins with a truncated 2-on-2 α-helical fold were discovered. Genomic information over the last 20 years has dramatically expanded the list of known globins, demonstrating their existence in a limited number of archaeal genomes, a majority of bacterial genomes and an overwhelming majority of eukaryote genomes. In vertebrates, 6 additional globin types were identified, namely neuroglobin (Ngb), cytoglobin (Cygb), globin E (GbE), globin X (GbX), globin Y (GbY) and androglobin (Adgb). Furthermore, functions beyond the familiar oxygen transport and storage have been discovered within the vertebrate globin family, including NO metabolism, peroxidase activity, scavenging of free radicals, and signaling functions. The extension of the knowledge on globin functions suggests that the original roles of bacterial globins must have been enzymatic, involved in defense against NO toxicity, and perhaps also as sensors of O 2 , regulating taxis away or towards high O 2 concentrations. In this review, we aimed to discuss the evolution and remarkable functional diversity of vertebrate globins with particular focus on the variety of non-canonical expression sites of mammalian globins and their according impressive variability of atypical functions.

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Section: Cytoglobinmentioning

confidence: 99%

Section: Cytoglobinmentioning

confidence: 99%

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

et al. 2020

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“…Our results add to a growing list of reported Crb1 rd8 modifier genes, which include Cx3cr1, Mthfr, Crb2, Cygb, Jak3, and Nfe2l2 [35], [39][40][41][42][43], [45]. Analysis of modifier genes in mouse models of other diseases have been useful for assembling genetic networks that provide important clues to pathogenesis and offer new avenues for therapeutic intervention [31], [32].…”

Section: Discussionmentioning

confidence: 63%

“…These efforts may be amplified by the characterization of retinal dysplasia among B6N-derived strains generated by the Knockout Mouse Phenotyping Program and International Mouse Phenotyping Consortium, where every knock-out line also bears the Crb1 rd8 mutation [92], [93]. The potential of this second approach has been demonstrated [40].…”

Section: Discussionmentioning

confidence: 99%

Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1^rd8 Mouse Model

Weatherly

Collin

Charette

et al. 2021

Preprint

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Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. In both models at one month of age, Müller glia and microglia mislocalization at dysplastic lesions was similar to that in B6.Cg-Crb1rd8/Pjn mice, while photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms.

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“…Variability of the dysplastic phenotype was also noted among mice derived from the C57BL/6N (B6N) substrain, which is homozygous for the Crb1 rd8 allele [ 36 ], and in strains from The Jackson Laboratory (JAX) collection [ 37 ]. Cx3cr1 , Mthfr , and Cygb were identified as modifiers of Crb1 rd8 retinal dysplasia [ 38 – 40 ], Jak3 as an enhancer of a Crb1 rd8 -dependent neovascular phenotype [ 41 ], and Crb2 as a modifier of retinal dysplasia due to a Crb1 knock-out allele [ 42 , 43 ]. Further, the choroidal neovascularization phenotype of an Nfe2l2 knock-out strain [ 44 ] was more severe in the presence of homozygous Crb1 rd8 alleles [ 45 ], indicating gene interaction.…”

Section: Introductionmentioning

confidence: 99%

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

et al. 2022

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Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans.

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Cytoglobin deficiency potentiates Crb1-mediated retinal degeneration in rd8 mice

Cited by 10 publications

References 58 publications

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1^rd8 Mouse Model

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

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Cytoglobin deficiency potentiates Crb1-mediated retinal degeneration in rd8 mice

Cited by 10 publications

References 58 publications

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

Lessons from the post-genomic era: Globin diversity beyond oxygen binding and transport

Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1rd8 Mouse Model

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

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Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1^rd8 Mouse Model