Abstract
Purpose::
Ocular Albinism type I (OA1) is an X-linked recessive disease due to mutations in the OA1 gene, which is expressed in melanocytes and retinal pigment epithelium (RPE). The OA1 patients show visual abnormalities common to all forms of albinism including foveal hypoplasia that causes reduction in visual acuity, nystagmus and misrouting of optic fibers at the chiasm. Our aim is to characterize the visual system of Oa1-/- mice from the eye to the visual cortex to shed light on the pathophysiology of ocular albinism.
Methods::
First, we determined the expression pattern by in situ hybridization of the tyrosine kinase receptor (EphB1), a molecule implicated in axon guidance, in Oa1-/- retinae. Characterization of the thalamus-cortex projection in Oa1-/- mice was performed by analyses of the Arc expression in the cortex and a genetic labeling. To this end, we are currently mating Oa1-/- animals with Ror-α/Cre; Rosa26 transgenic mice expressing YFP specifically in the thalamo-cortical projections. In order to correlate the morphological findings functionally we assessed the activity of the Accessory Optic System (AOS) with the OpTomotry test and visual acuity with Prusky’s water task. Finally, to complement these data with gain of function experiments, we are currently performing Oa1 gene transfer to the fetal Oa1-/- retina with adeno-associated viral vectors (AAV) to test whether gene replacement is able to revert these abnormalities.
Results::
We observed a strong reduction of the EphB1 transcript in the ventro-temporal retina of Oa1-/- mice. This result correlates with the reduction of the retinal ganglion cells (RGCs) ipsilateral projection to the thalamus as assessed with cholera-toxin labeling. Arc transcript is up-regulated and partially mis-localized in Oa1-/- mice compared to wt littermates, allowing to precisely track the incoming fibers from the thalamus within visual cortex. We found a significant reduction of the activity of AOS in Oa1-/- mice, this may be due to a reduction of the ipsilateral component that innervates the AOS. Nevertheless, the visual acuity of Oa1-/- mice measured by water task behavioral test was similar between Oa1-/- and control animals.
Conclusions::
We found different anomalies affecting the visual system of Oa1-/- mice. This study will be instrumental to both get into the molecular bases of albinism and to fully appreciate the impact of gene-based therapies to correct the disease phenotype.
Keywords: visual cortex • retinal pigment epithelium • thalamus/lateral geniculate nucleus