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Originally published In Press as doi:10.1167/iovs.08-1806 on March 31, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3245-3252.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-1806
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Involvement of OA1, an Intracellular GPCR, and G{alpha}i3, Its Binding Protein, in Melanosomal Biogenesis and Optic Pathway Formation

Alejandra Young,1,2,3 Elisabeth B. Powelson,4 Irene E. Whitney,4 Mary A. Raven,4 Steven Nusinowitz,1 Meisheng Jiang,5 Lutz Birnbaumer,6 Benjamin E. Reese,4 and Debora B. Farber1,3

1From the Jules Stein Eye Institute and the 5Department of Molecular and Medical Pharmacology, University of California, Los Angeles School of Medicine; 3the Molecular Biology Institute at UCLA, Los Angeles, California; the 4Neuroscience Research Institute and Department of Psychology, University of California, Santa Barbara, California; and the 6Transmembrane Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.

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 G{alpha}i-subunit of heterotrimeric G-proteins from human melanocyte extracts. This study was undertaken to test whether one of the G{alpha}i proteins, G{alpha}i3, signals in the same pathway as OA1 to regulate melanosome biogenesis and axonal growth through the optic chiasm.

METHODS. Adult G{alpha}i3–/– and Oa1–/– mice were compared with their respective control mice (129Sv and B6/NCrl) to study the effects of the loss of G{alpha}i3 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 G{alpha}i3–/– 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 G{alpha}i3–/– and Oa1–/– mice showed abnormal melanosomes that were far larger than the largest 129Sv and B6/NCrl melanosomes, respectively. Although G{alpha}i3–/– 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 G{alpha}i3, like Oa1, plays an important role in melanosome biogenesis. Furthermore, they suggest a common Oa1-G{alpha}i3 signaling pathway that ultimately affects axonal growth through the optic chiasm.






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