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Sonia Guha, Kristen Lee, Melody Wang, Debora B Farber; The G-protein Coupled Receptor Oa1 Activates Creb Through G∝s to Modulate Doublecortin Expression in Developing Mouse Eyes. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3116.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular albinism type 1, caused by mutations in the OA1 gene, is characterized by the presence of giant melanosomes in retinal pigment epithelial cells and abnormal crossing of the retinal ganglion cells’ (RGCs) optic axons at the brain’s optic chiasm. Exactly how OA1, the protein product of the OA1 gene, exerts its effects on the RGCs to influence the routing of the optic axons remains unsolved. Compared to the B6/NCrl control, the Oa1 knockout mouse (Oa1-/-), an animal model for ocular albinism, has a 24% reduction in the number of ipsilateral RGC axons.The purpose of our studies was to determine if aberrant Oa1-cAMP response element binding protein (Creb) signaling contributes to the axon routing errors.
Western blots were used to compare the levels of G-protein alpha stimulatory subunit (G∝s), phosphorylated Creb (pCreb, the active form of Creb) and doublecortin (Dcx) in the posterior pole of developing control B6/NCrl and Oa1-/- mouse eyes and immunohistochemistry was performed to determine the difference in the spatiotemporal expression patterns of the same proteins.
Western blot and immunohistochemistry results showed a decrease in G∝s and pCreb in both the embryonic and postnatal eyes of Oa1-/- mice compared to those of control B6/NCrl animals. G∝s and pCreb were seen in both RPE and retina. At E15.5, a stage when retinal cells are not yet organized in different layers, the control B6/NCrl mouse retinas also showed strong immuno-reactivity for the microtubule binding protein, Dcx. In contrast, the Oa1-/- mouse retinas showed reduced expression of Dcx.
These data suggest that G∝s, pCreb and their down-stream target, Dcx, may be involved in early retinal neurogenesis and that down-regulation of the Oa1-G∝s-Creb pathway in Oa1-/- mice may affect the routing of RGC axons. Future studies will identify other associated proteins in the Oa1-Creb-Dcx signaling cascade.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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