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

Iwan Jones,Anna-Carin Hägglund,Leif Carlsson

doi:10.1242/dmm.028605

Abstract

ABSTRACTDevelopment 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.

Highlights

IntroductionReceived 11 November 2016; Accepted 5 January 2017 iris, ciliary body (CB) and associated drainage structures involving the trabecular meshwork (TM) and Schlemm’s canal
The lineage-traced ciliary margin (CM) cells were found to contribute to the ciliary epithelia (CE) of the ciliary body (CB) (Fig. 1D), the iris pigment epithelium (IPE) (Fig. 1E) and both sets of iridial muscles; the dilator pupillae (DP) and the sphincter pupillae (SP), respectively (Fig. 1E,F)
These studies could encompass histological and molecular analyses of the lens, cornea and associated drainage structures since aberrant development of these anterior eye tissues contributes to Anterior segment dysgenesis (ASD) presentation (Idrees et al, 2006; Ito and Walter, 2014)

Summary

Introduction

Received 11 November 2016; Accepted 5 January 2017 iris, ciliary body (CB) and associated drainage structures involving the trabecular meshwork (TM) and Schlemm’s canal Development of these tissues involves a complex interplay between neuroectodermal cells originating from the ciliary margin (CM) of the optic cup, neural crest cells residing within the overlying periocular mesenchyme (POM) and ectodermal lens epithelial (LE) cells. Ocular-specific ASD is a group of syndromes that solely affect the eye and its associated structures This group is best exemplified by aniridia which is a neuroectoderm-derived panocular disorder that is associated predominantly with mutations in paired box gene 6 (PAX6). The systemic forms of ASD are a group of closely related diseases with Axenfeld–Rieger syndrome (ARS) and Peter’s anomaly (PA) being amongst the best characterised Both are neural crest-derived disorders and result predominantly from mutations in either paired-like homeodomain 2 (PITX2) or forkhead box C1 (FOXC1). ARS and PA share common and highly penetrant anterior segment deficits that primarily affect the pupil and drainage structures (Cvekl and Tamm, 2004; Gould and John, 2002; Graw, 2010; Idrees et al, 2006; Ito and Walter, 2014; Lee et al, 2008; Reis and Semina, 2011; Sowden, 2007)

Methods

Results

Conclusion