Purpose
Myopia is the most common human eye disorder worldwide and high-grade myopia is one of the most frequent causes of blindness due to associated complications such as glaucoma. In man, mutations of the megalin encoding gene causes the extremely rare Donnai-Barrow/ Facio-Oculo-Acoustico-Renal Syndrome that is characterized by diverse clinical manifestations of which high-grade myopia has been consistently observed. Additional evidence supporting that megalin may play a role in development of myopia includes observations of adult-onset myopia in megalin-deficient zebrafish. Megalin is a multi-ligand endocytic receptor and extensive studies of renal proximal tubular epithelium have shown that megalin is crucial for conservation of filtered nutrients including vitamin D, vitamin A, vitamin B12 and iron. Megalin has previously been localized to the retina pigment epithelium (RPE) and ciliary body epithelium of the adult eye, however, the physiological role of megalin in these epithelia has not been clarified. The purpose of this study was to determine subcellular localization of megalin in the adult eye and, prospectively, also the physiological role.
Methods
Eye tissue from normal and megalin-deficient mice as well as normal human eye was examined with immunological techniques using confocal and electron microscopy to determine the topographical and subcellular localization of megalin.
Results
Megalin was identified in RPE cells and ciliary body non-pigmented epithelium (CBNPE) in both human and mouse adult eye. Immunocytochemical investigations of ultrathin cryosections of mouse eyes displayed a disperse, vesicle-like, cytoplasmic localization of megalin in RPE cells but a predominantly apical localization in CBNPE cells. Furthermore, histological cross sections of eyes from normal and megalin-deficient mice showed a severe increase in overall eye size and axial length (See figure) as well a thinning of the neural layers of the retina in mice deficient of megalin.
Conclusions
The topographical localization of megalin in the adult eye corresponds to the blood-aqueous humor and blood-retina barriers respectively. Based on our findings, megalin seems to be a prime candidate to mediate selective transport of nutrients to the inner structures of the eye. Finally, the increased axial length observed in the megalin-deficient mice supports findings from patients and zebrafish and suggests that the megalin-deficient mice may prove a valuable model for future studies of myopia.
Keywords: 605 myopia •
554 immunohistochemistry •
701 retinal pigment epithelium