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A. Onishi, D. Lee, E. Poth, U. Alexis, S. Blackshaw; Estrogen Receptor-Related Receptor β Mediate Photoreceptor Development and Survival. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4399. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Estrogen receptor-related receptor (ERR) β, one of three ERR subtypes (α, β and γ), is an orphan nuclear hormone receptor homologous to classical estrogen receptors. We have demonstrated that ERRβ is expressed rods and horizontal cells. We further clarify the cellular localization of ERRβ, and analyze the functional roles by gain and loss of function (GOF and LOF).
Antibodies against all identified ERR subtypes were used in combination with antibodies for major mature retinal cell types. GOF and LOF analyses were performed by in vivo electroporation. For GOF, both full-length ERRβ or VP16-ERRβ (dominant active form) expressed from the ubiquitous CAG promoter in conjunction with a bicistronic GFP into neonatal mouse retina were tested. For LOF, we introduced shRNA directed against ERRβ or EnR-ERRβ (dominant negative form). We also explanted P0/P14 retinas and cultured for 4-14 days in media containing 17β-estradiol (E2, no effect on ERRs), diethylstilbestrol (DES, inverse agonist for all ERR subtypes) or 4-hydroxytamoxifen (4-OHT, inverse agonist to ERRβ and ERRγ). Electroporated retinas or explants were analyzed by section and disassociated-cell immunocytochemistry in conjunction with specific markers of retinal cell subtypes. Explants were also analyzed by TUNEL staining and microarray.
ERRβ was selectively expressed in developing horizontal cells and mature rods (strongly expressed from P7), while ERRα and ERRγ were expressed in INL cells and cones, and weakly expressed in adult rods. GOF of ERRβ promoted rod development. Electroporated cells at inner ONL weakly expressed calbindin (horizontal cell marker). LOF by shRNA promoted Müllergenesis, and LOF by EnR-ERRβ promoted amacrine cell development. Explants exposed to DES looked normal until P7, and then resulted in progressive rod photoreceptor degeneration. Explants exposed to 4-OHT also showed retinal degeneration that was not severer than those exposed to DES. Explants electroporated with VP16-ERRβ could maintain the ONL in spite of exposure to DES/4-OHT. Microarray analyses revealed that DES/4-OHT selectively downregulated expression of a large number of photoreceptor-enriched genes, particularly genes involved in regulation of respiration and intracellular transport.
ERRβ positively regulates rod development, but does not directly regulate horizontal cell fate. Genes transactivated by ERRβ are necessary for maintenance and survival of mature rod photoreceptors and promote rod survival by a non-cell-autonomous pathway.
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