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Alejandra Young, Meisheng Jiang, Novruz B. Ahmedli, Debora B. Farber; A Constitutively Active G-alpha-i3 Corrects the Abnormal RPE Melanosomal Phenotype in Oa1 Knockout mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1629.
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Ocular Albinism type 1 (OA1) is a disease caused by mutations in the OA1 gene and characterized by macromelanosomes in the RPE and abnormal crossing of the optic axons at the optic chiasm. We have shown that in the Oa1 signalling pathway this G-protein-coupled receptor activates specifically Gαi3. We hypothesize that a constitutively active Gαi3 could by-pass the lack of Oa1 in the RPE of Oa1 knockout (Oa1-/-) mice and keep the Oa1 signalling cascade going, preventing in this way the formation of macromelanosomes. Therefore, we introduced into the Oa1-/- RPE a constitutively active Gαi3 (Q>L). If rescue of the abnormal RPE melanosomal phenotype of Oa1-/- mice occurred, it would be an in-vivo proof that Gαi3 is indeed the next step after Oa1 in the signalling cascade controlling pigmentation of the RPE.
Transgenic mice carrying a constitutively active Gαi3 (Q>L) protein were generated in the Oa1-/- background. Morphometrical analyses were performed using light and electron microscopy to compare the size and number of melanosomes per RPE area in putative Oa1-/-, Gαi3 (Q>L) transgenic mice with those of wild type B6/NCrl and Oa1-/- mice.
We found that there is a correlation between the presence of the transgene and the rescue of the normal phenotype of RPE melanosomes in the Oa1-/- mice carrying the constitutively active Gαi3. The Oa1-/-, Gαi3 (Q>L) transgenic mice have a higher density of melanosomes per RPE area and a larger number of small melanosomes than Oa1-/- mice and a similar RPE phenotype to that of wild type mice.
Our results show that a constitutively active Gαi3 protein can by-pass the lack of Oa1 in Oa1-/- mice and consequently rescue the normal RPE melanosomal phenotype.
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