Abstract
BackgroundRetinoic acid (RA) is important for vertebrate eye morphogenesis and is a regulator of photoreceptor development in the retina. In the zebrafish, RA treatment of postmitotic photoreceptor precursors has been shown to promote the differentiation of rods and red-sensitive cones while inhibiting the differentiation of blue- and UV-sensitive cones. The roles played by RA and its receptors in modifying photoreceptor fate remain to be determined.ResultsTreatment of zebrafish embryos with RA, beginning at the time of retinal progenitor cell proliferation and prior to photoreceptor terminal mitosis, resulted in a significant alteration of rod and cone mosaic patterns, suggesting an increase in the production of rods at the expense of red cones. Quantitative pattern analyses documented increased density of rod photoreceptors and reduced local spacing between rod cells, suggesting rods were appearing in locations normally occupied by cone photoreceptors. Cone densities were correspondingly reduced and cone photoreceptor mosaics displayed expanded and less regular spacing. These results were consistent with replacement of approximately 25% of positions normally occupied by red-sensitive cones, with additional rods. Analysis of embryos from a RA-signaling reporter line determined that multiple retinal cell types, including mitotic cells and differentiating rods and cones, are capable of directly responding to RA. The RA receptors RXRγ and RARαb are expressed in patterns consistent with mediating the effects of RA on photoreceptors. Selective knockdown of RARαb expression resulted in a reduction in endogenous RA signaling in the retina. Knockdown of RARαb also caused a reduced production of rods that was not restored by simultaneous treatments with RA.ConclusionsThese data suggest that developing retinal cells have a dynamic sensitivity to RA during retinal neurogenesis. In zebrafish RA may influence the rod vs. cone cell fate decision. The RARαb receptor mediates the effects of endogenous, as well as exogenous RA, on rod development.
Highlights
Retinoic acid (RA) is important for vertebrate eye morphogenesis and is a regulator of photoreceptor development in the retina
In zebrafish that are mutant for the tbx2b gene, encoding a transcription factor expressed in early retinal progenitors, the UV cones are conspicuously missing from the larval cone mosaic, their positions instead occupied by supernumerary rod photoreceptors [13], suggesting an alteration in cell fate choice by retinal progenitors
Sustained RA treatment beginning at the time of early retinal neurogenesis changes the ratio of rods to cones RA manipulations were performed beginning at 36 hpf, a time when much of the embryonic retina remains proliferative and no photoreceptors are definitively postmitotic [1]
Summary
Retinoic acid (RA) is important for vertebrate eye morphogenesis and is a regulator of photoreceptor development in the retina. In zebrafish that are mutant for the tbx2b gene, encoding a transcription factor expressed in early retinal progenitors, the UV cones are conspicuously missing from the larval cone mosaic, their positions instead occupied by supernumerary rod photoreceptors [13], suggesting an alteration in cell fate choice by retinal progenitors. Together these findings suggest some overlap of, or plasticity within, the progenitor cell populations otherwise fated to generate rods or cones
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