Otx2 Gene Deletion in Adult Mouse Retina Induces Rapid RPE Dystrophy and Slow Photoreceptor Degeneration

Abstract

BackgroundMany developmental genes are still active in specific tissues after development is completed. This is the case for the homeobox gene Otx2, an essential actor of forebrain and head development. In adult mouse, Otx2 is strongly expressed in the retina. Mutations of this gene in humans have been linked to severe ocular malformation and retinal diseases. It is, therefore, important to explore its post-developmental functions. In the mature retina, Otx2 is expressed in three cell types: bipolar and photoreceptor cells that belong to the neural retina and retinal pigment epithelium (RPE), a neighbour structure that forms a tightly interdependent functional unit together with photoreceptor cells.Methodology/Principal FindingsConditional self-knockout was used to address the late functions of Otx2 gene in adult mice. This strategy is based on the combination of a knock-in CreERT2 allele and a floxed allele at the Otx2 locus. Time-controlled injection of tamoxifen activates the recombinase only in Otx2 expressing cells, resulting in selective ablation of the gene in its entire domain of expression. In the adult retina, loss of Otx2 protein causes slow degeneration of photoreceptor cells. By contrast, dramatic changes of RPE activity rapidly occur, which may represent a primary cause of photoreceptor disease.ConclusionsOur novel mouse model uncovers new Otx2 functions in adult retina. We show that this transcription factor is necessary for long-term maintenance of photoreceptors, likely through the control of specific activities of the RPE.

Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

“…The finding that some transcription factors that are critical in RPE development are continuously expressed into mature stages raises the question as to what roles they play in adult RPE. It has been reported recently that tissue-specific inactivation of Otx2 in the mature retina and RPE led to abnormalities in the RPE, such as reduction of the number and size of melanosomes and a loss of RPE contacts with photoreceptor outer segments followed by retinal degeneration, revealing the essential role of OTX2 in maintaining the integrity of the adult RPE (16,55). OTX2 coordinates RPE-specific functions, such as retinoid metabolism and melanogenesis, and directly regulates several visual cycle-related genes, including Rdh5 (16).…”

The transcription factor Otx2 regulates choroid plexus development and function

“…As less proliferation occurs at this time, this effect is also likely to be due to many ChP cells undergoing cell death. Interestingly, in other systems loss of Otx2 also leads to an increase in apoptosis, such as in the adult mouse retinal pigment epithelium and photoreceptors and in GnRH neurons (Béby et al, 2010;Diaczok et al, 2011). These results imply a role for Otx2 as a key regulator of genes that are essential for the function and identity of these cells, such that they fail to survive without them, or the direct regulation by Otx2 of anti-apoptotic genes.…”

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

“…OTX2, a paired-type homeodomain protein, is important for specification and postmitotic function of PRs [73], bipolar neurons, and RPE [74][75][76][77]. OTX2 [+] cells first appear in the developing PRs, and then in the bipolar and RPE cells during mammalian retinogenesis [78].…”