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Lena Iwai, Anna Ramos, Richard Blazeski, Carol Mason; Perturbations of the developing albino mouse RPE during retinal ganglion cell genesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5164.
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During early eye development, the RPE is apposed to the neural retina. As the RPE acquires pigment, retinal ganglion cells (RGCs) are born and specified into two subpopulations, those that project their axons to the same (ipsilateral) or opposite (contralateral) side of brain to targets in the thalamus and midbrain. This divergent projection is the basis for binocular vision. In mice, the ipsilateral projection arises from the ventrotemporal (VT) retina during embryonic day (E) 14.5-E16.5. Our previous studies have identified genes that specify the two RGC subpopulations, including Zic2 and EphB1 for the ipsilateral projection. Albinism is characterized by diverse genetic defects that perturb either melanin synthesis or melanosome biogenesis in the RPE. A universal phenotype of albino mammals and humans is the reduction of the ipsilateral projection, in mice, reflected in fewer RGCs expressing Zic2. However, the molecular mechanisms that link melanin deficiencies in the RPE with a diminished ipsilateral RGC projection, especially the genes specifying the ipsilateral versus contralateral projection, are not understood. To begin to address this, we are investigating RPE development during RGC genesis in the albino and pigmented retina, focusing on RPE cell integrity and cell biology.
With immunohistochemistry, in situ hybridization and EM, we compared the morphological and cell biological features of the RPE in albino and pigmented embryonic retina (E13-17) in littermates generated from crosses between Tyr+/TyrC2J and TyrC2J/TyrC2J mice.
Cell shape, gap junction protein (Gja1) distribution, and polarity of melanosome localization are disrupted in the albino RPE, specifically in VT retina. Studies are ongoing to determine the transcription factors and candidate molecules important for communication with the neural retina that are deficient in albino RPE, and whether perturbations occur throughout the RPE or only in VT retina.
Our results suggest that perturbed RPE cell biology in the albino retina during RGC genesis may affect the integrity of the RPE and in turn, the release of factors affecting ipsilateral RGC specification. These studies should reveal how the RPE normally affects neural retinal development. This information can be applied to directing stem cells into RGCs for replacement in injured or degenerating visual pathways.
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