Plasticity of photoreceptor-generating retinal progenitors revealed by prolonged retinoic acid exposure

Sep 1, 2011BMC developmental biology

Changes in light-sensing cell precursors shown by long-term exposure to retinoic acid

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Abstract

Treatment of zebrafish embryos with retinoic acid (RA) altered rod and cone photoreceptor patterns, potentially replacing approximately 25% of red-sensitive cones with rods.

RA treatment increased the density of rod photoreceptors while reducing the density of red-sensitive cone photoreceptors.
The local spacing between rod cells decreased, indicating that rods were occupying areas typically filled by cones.
Cone photoreceptor mosaics became more irregular and expanded, correlating with a decrease in cone density.
Multiple retinal cell types can respond directly to RA, suggesting a broad influence on retinal development.
The RA receptors RXRγ and RARαb are present in patterns that align with their roles in photoreceptor development.
Knockdown of RARαb led to decreased rod production, indicating its critical role in mediating RA's effects on rod development.

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BACKGROUND: Retinoic 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.

RESULTS: Treatment 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.

CONCLUSIONS: These 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.

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Plasticity of photoreceptor-generating retinal progenitors revealed by prolonged retinoic acid exposure

Abstract

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