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A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development.

ABSTRACT: Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of Tsc1 during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, Bmp4 and Msx1 Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies Tsc1 as a novel candidate ASD gene. Furthermore, the Tsc1-ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.

SUBMITTER: Hagglund AC

PROVIDER: S-EPMC5374326 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of <i>Tsc1</i> disrupts ciliary body and iris development.

Hägglund Anna-Carin AC Jones Iwan I Carlsson Leif L

Disease models & mechanisms 20170301 3

Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and sy ...[more]

PMID: 28250050

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Project description:Fuchs uveitis (FU) is a chronic and often unilateral ocular inflammation and characteristic iris atrophic changes, other than heterochromia, are common in FU and are key to the correct diagnosis in many cases. With the advent of anterior segment optical coherence tomography (AS-OCT), some investigators attempted to quantitatively study these atrophic changes; mostly by introducing various methods to measure iris thickness in AS-OCT images. We aimed to present an automated method in an observational case series to measure the smoothness index (SI) of the iris surface in AS-OCT images. The ratio of the length of the straight line connecting the most peripheral and central points of the anterior iris border (in nasal and temporal sides) to the actual length of this border on AS-OCT images, was defined as SI. In a uveitis referral center, twenty-two eyes of 11 patients with unilateral Fuchs uveitis (FU) (7 female) and 22 eyes of 11 healthy control subjects underwent AS-OCT imaging. Image J and a newly developed MATLAB algorithm were used for manual and automated SI measurements, respectively. Agreement between manual and automated measurements was evaluated with Bland-Altman analysis and interclass correlation coefficient. The inter-eye difference of SI was compared between the FU group and the control group. Automated mean overall SI was 0.868 ± 0.037 and 0.840 ± 0.039 in FU and healthy fellow eyes, respectively (estimated mean difference = - 0.028, 95% CI [- 0.038, - 0.018], p < 0.001). Bland- Altman plots showed good agreement between two methods in both healthy and FU eyes. The interclass correlation coefficient between the manual and automated measurements in the FU and healthy fellow eyes was 0.958 and 0.964, respectively. The inter-eye difference of overall SI was 0.029 ± 0.015 and 0.012 ± 0.008 in FU group and control group, respectively (p = 0.01). We concluded that the automated algorithm can rapidly and conveniently measure SI with results comparable to the manual method.

Dataset Information

A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of Tsc1 disrupts ciliary body and iris development.

Publications

A novel mouse model of anterior segment dysgenesis (ASD): conditional deletion of <i>Tsc1</i> disrupts ciliary body and iris development.

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