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D. L. Stenkamp, C. B. Stevens, B. Kashyap, D. A. Cameron; New Roles for Retinoic Acid (RA) Signaling in Zebrafish Retinal Development. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3736.
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Known functions for RA signaling in retinal development include early roles in eye morphogenesis and later roles in photoreceptor differentiation (Hyatt and Dowling, 1997, IOVS 38:1471-5). Endogenous RA signaling also takes place within the eye at intermediate times, during retinal histogenesis (Marsh-Armstrong et al., 1994, PNAS 91:7286-90). We wished to determine the function of RA signaling at this time, and whether elevated RA signaling rescues ocular effects of ethanol treatment, in a zebrafish model for fetal alcohol syndrome (Kashyap et al., 2007, Vis Neurosci 24:409-21).
Embryonic zebrafish were treated with RA and/or ethanol, and eyes and lenses of fixed embryos were measured. Embryos were processed as whole mounts or as cryosections for immunocytochemistry and in situ hybridization for retinal cell-specific markers. Two-dimensional patterns of labeled photoreceptors were evaluated by three independent analytical methods.
RA treatment at the beginning of retinal histogenesis (24-48 hours post-fertilization; hpf) resulted in decreased retinal proliferation, and greatly reduced eye size. These treatments did not rescue the microphthalmic effects of concomitant treatment with ethanol. However, co-treatment with RA during retinal histogenesis (24-48 hpf) did rescue or override the deleterious effects of ethanol on subsequent photoreceptor differentiation. Initiation of RA treatment later in retinal histogenesis, but prior to terminal mitosis of photoreceptors (36-75 hpf), did not alter retinal cell death or proliferation, but did result in the elevated production of rod photoreceptors and reduced production of cones. Statistical analyses of the patterns of the rods and red cones were consistent with a possible cone-to-rod fate change, a striking observation given that later RA treatments (48-75 hpf) did not influence photoreceptor fate (Prabhudesai et al., 2005, Dev Biol 287:157-67).
Our studies revealed multiple, temporally-selective effects of RA during retinal development. Early in retinal histogenesis RA reduces cell proliferation, while later treatments influence photoreceptor fate. Still later treatments alter the rates of photoreceptor differentiation in a cell-targeted manner (Prabhudesai et al., 2005). Finally, our studies suggest that most of the effects of ethanol treatment on retinal development are not mediated by disruption of RA signaling mechanisms.
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