Collin, G. B. | Search bioRxiv

bioRxiv2022

Comparative and longitudinal analysis of axial and retinal biometry in prospective models of hyperopia

Structured AbstractO_ST_ABSPurposeC_ST_ABSTo quantify changes in axial and retinal biometry in aging hyperopic mouse models. MethodsFundus photographs and ocular biometric measurements from Mfrprd6, Prss56glcr4, Adipor1tm1Dgen, C1qtnf5tm1.1(KOMP)Vlcg and Prss56em2(IMPC)J homozygotes and C57BL/6J control mice were ascertained longitudinally up to one year of age. Parameters including axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), outer nuclear layer thickness (ONLT), retinal thickness (RT), vitreous chamber depth (VCD) and posterior length (PL) were measured using Spectral Domain-Optical Coherence Tomography imaging. Mixed-model analysis of variance and factorial analysis of covariance, using body size as a covariate, followed by post-hoc analysis was performed to identify significant strain differences. ResultsStrain specific changes in axial and retinal biometry along with significant effects of age, sex and body size on AL were noted. Mfrprd6, Prss56glcr4, Adipor1tm1Dgen and Prss56em2(IMPC)J homozygotes had significantly shorter AL than controls. While a comparable decrease in PL was observed in Mfrprd6, Prss56glcr4, and Adipor1tm1Dgen homozygotes, the decrease was attributed to changes in different posterior components from each mutant. Mfrprd6 and Adipor1tm1Dgen homozygotes developed regularly sized fundus spots across the ocular globe, which differed from the large bright spots seen in aged Prss56glcr4 and Prss56em2(IMPC)J homozygotes. While ONLT of C1qtnf5tm1.1(KOMP)Vlcg mice was less than controls, AL and fundus images appeared normal. ConclusionsThis study highlights differences in contributions of ocular components to AL among hyperopic mouse models with decreased AL. Understanding the mechanisms through which these proteins function, will help to elucidate their role in controlling ocular growth.

genetics↗

bioRxiv2021

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

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, Muller 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.

genetics↗