Identification of Apolipoprotein A-I as a “STOP” Signal for Myopia

Eric Bertrand,Katrina L Schmid,Hans Voshol,Jan Van Oostrum,Sigrid Diether,Patrick Schindler,Frank Schaeffel,Christine Fritsch,George Lambrou,Dieter Müller

doi:10.1074/mcp.m600073-mcp200

Eric Bertrand, Katrina L Schmid + Show 8 more

Open Access

https://doi.org/10.1074/mcp.m600073-mcp200

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Abstract

Good visual acuity requires that the axial length of the ocular globe is matched to the refractive power of the cornea and lens to focus the images of distant objects onto the retina. During the growth of the juvenile eye, this is achieved through the emmetropization process that adjusts the ocular axial length to compensate for the refractive changes that occur in the anterior segment. A failure of the emmetropization process can result in either excessive or insufficient axial growth, leading to myopia or hyperopia, respectively. Emmetropization is mainly regulated by the retina, which generates two opposite signals: "GO/GROW" signals to increase axial growth and "STOP" signals to block it. The presence of GO/GROW and STOP signals was investigated by a proteomics analysis of the retinas from chicken with experimental myopia and hyperopia. Of 18 differentially expressed proteins that were identified, five displayed an expression profile corresponding to GO/GROW signals, and two corresponded to STOP signals. Western blotting confirmed that apolipoprotein A-I (apoA-I) has the characteristics of a STOP signal both in the retina as well as in the fibrous sclera. In accordance with this, intraocular application of the peroxisome proliferator-activated receptor alpha agonist GW7647 resulted in up-regulation of apoA-I levels and in a significant reduction of experimental myopia. In conclusion, using a comprehensive functional proteomics analysis of chicken ocular growth models we identified targets for ocular growth control. The correlation of elevated apoA-I levels with reduced ocular axial growth points toward a functional relationship with the observed morphological changes of the eye.

Highlights

Good visual acuity requires that the axial length of the ocular globe is matched to the refractive power of the cornea and lens to focus the images of distant objects onto the retina
The expression levels of a STOP signal should be increased in response to myopic defocus, and an induction of this signal should reduce the excessive axial growth induced by experimental myopia
Because our primary focus was on STOP signals, apolipoprotein A-I (apoA-I) was selected for confirmation studies by antibody-based methods

Summary

Introduction

Good visual acuity requires that the axial length of the ocular globe is matched to the refractive power of the cornea and lens to focus the images of distant objects onto the retina. Applying negative lenses over the eye of the chicken places the focal plane behind the retina (hyperopic defocus), accelerates axial eye growth, and leads to a myopic condition (lens induced myopia (LIM)). Applying positive lenses places the focal plane before the retina (myopic defocus), slows down axial eye growth, and leads to a hyperopic condition (lens induced hyperopia (LIH)). The expression levels of a STOP signal should be increased in response to myopic defocus (e.g. positive lenses), and an induction of this signal should reduce the excessive axial growth induced by experimental myopia. The levels of a GO/GROW signal should be increased in response to hyperopic defocus (e.g. negative lenses) or form deprivation, and an induction of this signal should exacerbate the axial growth induced by experimental myopia. We looked systematically for proteins up-regulated in response to myopic defocus and demonstrated that apoA-I functions as a STOP signal by its capability to inhibit excessive ocular axial growth

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