for the proper repression of rh6 in outer photoreceptors and for rhabdomere morphogenesis [42]. Therefore, in both mammals and flies, an Otd/Otx family transcription factor appears to repress the expression of color-sensitive opsins in dim-light and motion detection photoreceptors. The recruitment of Otd for this function might relate to its role is early specification of anterior segments, which include the eye in vertebrates and the ocular segments in flies.

Photoreceptor and Rhodopsin Specification in Flies and Mammals:

Different Mechanisms

A second transcription factor that controls the distinction between rods and cones is the bZIP (basic leucine zipper domain) protein NRL (neural retina leucine zipper). NRL positively regulates rod specification, in part by negatively regulating the transcription of cone genes in rods [59]. When NRL is removed in nrl−/− mice, the number of colorsensing cones (S cones) increases, while rod function is completely lost. This occurs because presumptive rods transform into “rod-cone” intermediates that exhibit hybrid rod-cone morphology but function as S cones because they express S-cone opsins [59]. Missense mutations in the NRL gene are associated with autosomal dominant retinitis pigmentosa, which further confirms a role for NRL in human photoreceptor development [60]. The nuclear hormone receptor Nr2E3 has also been implicated in the transcriptional regulation of photoreceptor subtype-specific genes. In a mouse model for retinal degeneration (rd7 mouse), more S cones are again present, while the number of rods is substantially decreased [60]. Nr2e3 may act in presumptive rod photoreceptors already expressing NRL to both activate a subset of rod specific genes and repress cone genes, including color-sensitive S-opsin [61].

A fourth gene that regulates mammalian rhodopsin expression is the thyroid hormone receptor TRβ2. It acts not by directly regulating the rod-cone decision but by controlling cone subtypes (Ng). TRβ2 mouse knockouts and cell culture showed that TRβ2 activates M-opsin and inhibits S-opsin, likely by reading a gradient of thyroid hormone during development [62, 63].

There are no known orthologs of NRL or TRβ2 in flies, and the only Drosophila ortholog of Nr2e3 has not been examined for eye function. Reciprocally, the two genes warts and melted play a critical role in the fly retina for specification of color photoreceptor subtypes, but it is unknown if their mammalian orthologs are involved in rhodopsin expression or if their mutations can cause human retinal pathologies. It is tempting to make a broad analogy between the role of NRL or NR2E3 with that of Drosophila prospero, which keeps particular color-sensitive rhodopsins repressed while simultaneously directing other aspects of photoreceptor morphogenesis [39]. Yet, the way these mammalian genes specify photoreceptors and regulate rhodopsin expression ultimately reflects the large mechanistic differences expected from two independently evolved eye systems.

CONCLUSION

Much has been learned about the molecular mechanisms that underlie Drosophila color vision, especially regarding molecular properties and developmental patterning

of Rh5 and Rh6. In addition to increasing our understanding of the molecular basis of color vision, these insights allow one to manipulate the expression of all Drosophila rhodopsins and genetically encode neural activity reporters or inactivate individual neurons in the fly brain. When combined, these experimental technologies provide powerful tools for research into exciting, but unknown, areas such as color-dependent behaviors, how inputs are computed to form color perceptions, and the neural circuits responsible for color processing.

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