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Alejandra Young, Elisabeth B. Powelson, Irene E. Whitney, Mary A. Raven, Steven Nusinowitz, Meisheng Jiang, Lutz Birnbaumer, Benjamin E. Reese, Debora B. Farber; Involvement of OA1, an Intracellular GPCR, and Gαi3, Its Binding Protein, in Melanosomal Biogenesis and Optic Pathway Formation. Invest. Ophthalmol. Vis. Sci. 2008;49(7):3245-3252. doi: https://doi.org/10.1167/iovs.08-1806.
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purpose. Ocular albinism type 1 (OA1) is characterized by abnormalities in retinal pigment epithelium (RPE) melanosomes and misrouting of optic axons. The OA1 gene encodes a G-protein-coupled receptor (GPCR) that coimmunoprecipitates with the Gαi-subunit of heterotrimeric G-proteins from human melanocyte extracts. This study was undertaken to test whether one of the Gαi proteins, Gαi3, signals in the same pathway as OA1 to regulate melanosome biogenesis and axonal growth through the optic chiasm.
methods. Adult Gαi3 −/− and Oa1 −/− mice were compared with their respective control mice (129Sv and B6/NCrl) to study the effects of the loss of Gαi3 or Oa1 function. Light and electron microscopy were used to analyze the morphology of the retina and the size and density of RPE melanosomes, electroretinograms to study retinal function, and retrograde labeling to investigate the size of the uncrossed optic pathway.
results. Although Gαi3 −/− and Oa1 −/− photoreceptors were comparable to those of the corresponding control retinas, the density of their RPE melanosomes was significantly lower than in control RPEs. In addition, the RPE cells of Gαi3 −/− and Oa1 −/− mice showed abnormal melanosomes that were far larger than the largest 129Sv and B6/NCrl melanosomes, respectively. Although Gαi3 −/− and Oa1 −/− mice had normal results on electroretinography, retrograde labeling showed a significant reduction from control in the size of their ipsilateral retinofugal projections.
conclusions. These results indicate that Gαi3, like Oa1, plays an important role in melanosome biogenesis. Furthermore, they suggest a common Oa1-Gαi3 signaling pathway that ultimately affects axonal growth through the optic chiasm.
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