Photoreceptor cKO of OTX2 Enhances OTX2 Intercellular Transfer in the Retina and Causes Photophobia

Abstract

In the mature mouse retina, <i>Otx2</i> is expressed in both retinal pigmented epithelium (RPE) and photoreceptor (PR) cells, and <i>Otx2</i> knock-out (KO) in the RPE alone results in PR degeneration. To study the cell-autonomous function of OTX2 in PRs, we performed PR-specific <i>Otx2</i> KO (cKO) in adults. As expected, the protein disappears completely from PR nuclei but is still observed in PR inner and outer segments while its level concomitantly decreases in the RPE, suggesting a transfer of OTX2 from RPE to PRs in response to <i>Otx2</i> ablation in PRs. The ability of OTX2 to transfer from RPE to PRs was verified by viral expression of tagged-OTX2 in the RPE. Transferred OTX2 distributed across the PR cytoplasm, suggesting functions distinct from nuclear transcription regulation. PR-specific <i>Otx2</i> cKO did not alter the structure of the retina but impaired the translocation of PR arrestin-1 on illumination changes, making mice photophobic. RNA-seq analyses following <i>Otx2</i> KO revealed downregulation of genes involved in the cytoskeleton that might account for the arrestin-1 translocation defect, and of genes involved in extracellular matrix (ECM) and signaling factors that may participate in the enhanced transfer of OTX2. Interestingly, several RPE-specific OTX2 target genes involved in melanogenesis were downregulated, lending weight to a decrease of OTX2 levels in the RPE following PR-specific <i>Otx2</i> cKO. Our study reveals a new role of endogenous OTX2 in PR light adaptation and demonstrates the existence of OTX2 transfer from RPE to PR cells, which is increased on PR-specific <i>Otx2</i> ablation and might participate in PR neuroprotection.