Abstract
The signaling molecule retinoic acid (RA) regulates rod and cone photoreceptor fate, differentiation, and survival. Here we elucidate the role of RA in differential regulation of the tandemly-duplicated long wavelength-sensitive (LWS) cone opsin genes. Zebrafish embryos were treated with RA from 48 hours post-fertilization (hpf) to 75 hpf, and RNA was isolated from eyes for microarray analysis. ~170 genes showed significantly altered expression, including several transcription factors and components of cellular signaling pathways. Of interest, the LWS1 opsin gene was strongly upregulated by RA. LWS1 is the upstream member of the tandemly duplicated LWS opsin array and is normally not expressed embryonically. Embryos treated with RA 48 hpf to 100 hpf or beyond showed significant reductions in LWS2-expressing cones in favor of LWS1-expressing cones. The LWS reporter line, LWS-PAC(H) provided evidence that individual LWS cones switched from LWS2 to LWS1 expression in response to RA. The RA signaling reporter line, RARE:YFP indicated that increased RA signaling in cones was associated with this opsin switch, and experimental reduction of RA signaling in larvae at the normal time of onset of LWS1 expression significantly inhibited LWS1 expression. A role for endogenous RA signaling in regulating differential expression of the LWS genes in postmitotic cones was further supported by the presence of an RA signaling domain in ventral retina of juvenile zebrafish that coincided with a ventral zone of LWS1 expression. This is the first evidence that an extracellular signal may regulate differential expression of opsin genes in a tandemly duplicated array.
Highlights
Color vision in vertebrates requires the differentiation of multiple types of cone photoreceptors in the retina, each of which has a different spectral sensitivity
The tandemly-replicated long wavelength-sensitive/medium wavelength-sensitive (LWS/MWS) array underlies trichromatic color vision; defects in these genes result in color blindness and X-linked retinal degenerations
We identified genes that were differentially expressed in zebrafish embryo eyes in response to treatment with the developmental signaling molecule retinoic acid (RA) during photoreceptor differentiation
Summary
Color vision in vertebrates requires the differentiation of multiple types of cone photoreceptors in the retina, each of which has a different spectral sensitivity. There are five major types of photoreceptor opsins in vertebrates: RH1 (rod opsin), SWS1 (short wavelength-sensitive; blue or UV), SWS2 (short wavelength-sensitive; blue), RH2 (middle wavelength-sensitive; green), and M/LWS (middle to long wavelengthsensitive, green or red) [2]. The human retina contains rods, which express rod opsin, as well as cones, which express one of three types of cone opsin, SWS1 (blue), MWS (green), and LWS (red). By comparison, the retina contains rods as well as four major classes of cones, SWS1 (UV), SWS2 (blue), RH2 (green), and LWS (red). The LWS and MWS opsin genes are arrayed in a tail to head manner on the X chromosome, the consequence of tandem gene duplication and evolutionary neofunctionalization [4]. The zebrafish LWS1 gene is orthologous to the human LWS gene, but the LWS/MWS gene duplication in humans is independent from the LWS1/ LWS2 duplication in zebrafish [3]
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