Abstract
The retinal pigment epithelium (RPE) shares its developmental origin with the neural retina (NR). When RPE development is disrupted, cells in the presumptive RPE region abnormally differentiate into NR-like cells. Therefore, the prevention of NR differentiation in the presumptive RPE area seems to be essential for regionalizing the RPE during eye development. However, its molecular mechanisms are not fully understood. In this study, we conducted a functional inhibition of a transcription factor Otx2, which is required for RPE development, using early chick embryos. The functional inhibition of Otx2 in chick eyes, using a recombinant gene encoding a dominant negative form of Otx2, caused the outer layer of the optic cup (the region forming the RPE, when embryos normally develop) to abnormally form an ectopic NR. In that ectopic NR, the characteristics of the RPE did not appear and NR markers were ectopically expressed. Intriguingly, the repression of Otx2 function also caused the ectopic expression of Fgf8 and Sox2 in the outer layer of the optic cup (the presumptive RPE region of normally developing eyes). These two factors are known to be capable of inducing NR cell differentiation in the presumptive RPE region, and are not expressed in the normally developing RPE region. Here, we suggest that Otx2 prevents the presumptive RPE region from forming the NR by repressing the expression of both Fgf8 and Sox2 which induce the NR cell fate.
Highlights
The retinal pigment epithelium (RPE), one component of the vertebrate eye, consists of a monolayer of melanin-producing cells
The development of the RPE is promoted by several transcription factors, which are expressed in the presumptive RPE region; Microphthalmia-associated transcription factor (Mitf) and Orthodenticle homeobox 1 and 2 (Otx1 and 2)
In HH10 chick embryos, Otx2 was expressed in a large part of the optic vesicle (OV), its expression was weak in the ventral part of the OV
Summary
The retinal pigment epithelium (RPE), one component of the vertebrate eye, consists of a monolayer of melanin-producing cells. In mutant mice with non-functional alleles of the Mitf gene, a non-pigmented NR-like tissue is ectopically formed in the outer layer of the OC [4,5]. The expression of Mitf in the presumptive RPE region requires the function of Otx genes [6]. Compound mutations in Otx and 2 (all Otx12/2; Otx2+/2 mice and 30% of Otx1+/2; Otx2+/2 mice) result in the down-regulation of Mitf expression and the ectopic formation of NR-like tissue in the outer layer of the OC, Otx12/2 mice do not display significant defects in the RPE [6]. In cultured quail retina cells, transfection of Otx induces a pigmented phenotype with Mitf expression [9]
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