Foxg1-Cre Mediated Lrp2 Inactivation in the Developing Mouse Neural Retina, Ciliary and Retinal Pigment Epithelia Models Congenital High Myopia.

Olivier Cases,Stéphane Lehéricy,Annabel Christ,Pascal Cosette,Sirine Ben-Yacoub,Sabine Amsellem-Levera,Antoine Joseph,Thomas Debeir,Manuel Simonutti,Antoine Obry,Fernando De Castro,Renata Kozyraki,Michel Pâques,Mathieu D Santin,José Alain Sahel,Ana Bribian,Sébastien Augustin

doi:10.1371/journal.pone.0129518

Abstract

Myopia is a common ocular disorder generally due to increased axial length of the eye-globe. Its extreme form high myopia (HM) is a multifactorial disease leading to retinal and scleral damage, visual impairment or loss and is an important health issue. Mutations in the endocytic receptor LRP2 gene result in Donnai-Barrow (DBS) and Stickler syndromes, both characterized by HM. To clearly establish the link between Lrp2 and congenital HM we inactivated Lrp2 in the mouse forebrain including the neural retina and the retinal and ciliary pigment epithelia. High resolution in vivo MRI imaging and ophthalmological analyses showed that the adult Lrp2-deficient eyes were 40% longer than the control ones mainly due to an excessive elongation of the vitreal chamber. They had an apparently normal intraocular pressure and developed chorioretinal atrophy and posterior scleral staphyloma features reminiscent of human myopic retinopathy. Immunomorphological and ultrastructural analyses showed that increased eye lengthening was first observed by post-natal day 5 (P5) and that it was accompanied by a rapid decrease of the bipolar, photoreceptor and retinal ganglion cells, and eventually the optic nerve axons. It was followed by scleral thinning and collagen fiber disorganization, essentially in the posterior pole. We conclude that the function of LRP2 in the ocular tissues is necessary for normal eye growth and that the Lrp2-deficient eyes provide a unique tool to further study human HM.

Highlights

Myopia usually results from an eye that has become too long, generally through elongation of the vitreous chamber
High-resolution small animal magnetic resonance imaging (MRI) revealed that the excessive eye enlargement was associated with a shorter inter-ocular distance and that the retrobulbar space; i.e. the space between the eyeball and the orbit, was reduced in the mutant eyes (Fig 1G–1J)
In the present study we show that Lrp2 expressed in the anterior neuroepithelium and its derivatives the neural retina, ciliary and retinal pigment epithelium is required for normal eye growth

Summary

Introduction

Myopia usually results from an eye that has become too long, generally through elongation of the vitreous chamber. It is a major health issue because of its increasing prevalence worldwide and the vision-threatening pathologies associated with high myopia (HM) [1,2]. HM affects 1%-3% of the population and is defined as refractive error greater than -6 diopters with axial eye length more than 26 mm [3,4]. In addition to the genetic mutations that influence the size of the eye the clinical state of the highly myopic globe depends on age and exposure to environmental factors. Highly myopic eyes are especially susceptible to develop degenerative changes including myopic chorioretinal atrophy and posterior staphyloma, complications that can cause visual loss [2,7–9]. It is currently difficult to control the progression of HM, to prevent or treat its associated complications and further comprehension of its pathogenesis is hampered by the lack of a genetic animal model that mimics the human pathology [10]

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Conclusion