Abstract
Purpose :
Fanconi anemia (FA) is a rare genetic disorder mainly associated with bone marrow failure and a propensity to tumor formation. However, frequent ocular manifestations have been reported in patients with FA. They include micro-ophthalmia, ptosis, and reduced optic disc. FA gene products like the FancC protein are critical in major cell events including cell division, DNA repair and autophagy. The aim of this study was to determine whether FancC-/- mice could be used as a model to study developmental ocular impairments found in FA.
Methods :
In adult FancC-/-, FancC+/- and Wild-type (WT) C57BL/6J mice, retinal function changes were monitored by electroretinogram (ERG) recordings at ~80-90 days of life. The histological development of retinal cell layers was studied by immunofluorescence. To this purpose, specific cell markers were used to visualize neuronal subpopulations: RNA-binding protein with multiple splicing (RBPMS) for retinal ganglion cells (RGCs), Choline acetyltransferase (ChAT) for starburst amacrine cells, PKCα for rod bipolar cells, Tyrosine hydroxylase (TH) for dopaminergic amacrine cells and recoverin for photoreceptors.
Results :
All FancC-/- mice presented external ocular anomalies such as apparent bilateral anophthalmia (3 mice), apparent unilateral anophthalmia (8 mice), unilateral micro-ophthalmia (8 mice) compared with WT (20 mice) and heterozygous animals (22 mice) that appeared normal. ERG recordings in visibly normal FancC-/- eyes did not show significant a-wave and b-wave amplitude reduction compared to other genotypes, suggesting that FancC is dispensable for the retinal function. Nevertheless, ERG measurements showed more variability between animals within the FancC-/- group than WT and FancC+/- littermates. Apparent anophthalmia turned out to be severe micro-ophthalmia, whose vestigial eyes were removed from the depth of the orbit and examined histologically. Their atrophied retinae contained folded and irregular cell layers composed of RBPMS-positive RGCs, ChAT-labelled starburst amacrine cells, PKCα-stained bipolar cells and recoverin-positive photoreceptors. In normally formed FancC-/- eyes, the dorsoventral length of the retina, and the number of RGCs and amacrine cells did not differ from those of the two other groups.
Conclusions :
Our data suggest that FancC-/- mice are a good model to study developmental ocular impairments associated with FA.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.