Involvement of OA1, an intracellular GPCR, and G alpha i3, its binding protein, in melanosomal biogenesis and optic pathway formation.
OBJECTIVE
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.
Young
Alejandra
A
Jules Stein Eye Institute, University of California, Los Angeles School of Medicine, Los Angeles, California 90095, USA.
Powelson
Elisabeth B
EB
Whitney
Irene E
IE
Raven
Mary A
MA
Nusinowitz
Steven
S
Jiang
Meisheng
M
Birnbaumer
Lutz
L
Reese
Benjamin E
BE
Farber
Debora B
DB
D000818:Animals; D001369:Axons / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D004596:Electroretinography; D005136:Eye Proteins / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000172:deficiency / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D020460:Melanosomes / Q000502:physiology* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009897:Optic Chiasm / Q000502:physiology*; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000502:physiology* / Q000648:ultrastructure; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission; D014795:Visual Pathways / Q000166:cytology / Q000254:growth & development / Q000502:physiology
D002352:Carrier Proteins; D005136:Eye Proteins; C506821:Gpr143 protein, mouse; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse