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Ana Maria Olivares, Yinan Han, David Soto, Kyle Flattery, Joe Marini, Pascal Escher, Margaret M DeAngelis, Neena B Haider; The nuclear hormone receptor gene Nr2c1 (Tr2) is a Critical Regulator of Cone Photoreceptor Cell Patterning. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4639.
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© ARVO (1962-2015); The Authors (2016-present)
Nr2c1 is a nuclear hormone receptor gene with no known function in the retina. Our preliminary studies show that Nr2c1 is regulated by, and functions in the Nr2e3 gene network in the developing and mature retina. The purpose of the study is to determine the gene networks and biological processes regulated by Nr2c1 in the retina.
An Nr2c1 knockout mouse was made in the 129S4/SvJaeJ genetic background using gene trap technology. Chimeric mice were backcrossed to C57BL/6 to generate B6 congenic animals. Mice were characterized at intermediate generations (F2, N1, N3, N10) clinically by indirect ophthalmoscopy and fluorescein angiography, functionally by ERG analysis, and histologically by H&E staining, electron microscopy, and immunohistochemistry. Molecular characterization was performed by chromatin immunoprecipitation and qPCR to identify gene targets of Nr2c1 in the developing and mature retina.
NR2C1 is localized to the outer neuroblastic layer in the embryonic retina and the outer nuclear layer, inner nuclear layer, and outer plexiform layer in the adult retina. Nr2c1 expression peaked at embryonic day 14 that correlates with peak generation of cones, ganglion, and amacrine cells. Examination of incipient congenic mice at N1, N3, and congenic mice at N10 revealed a retinal phenotype in N1 and N3 mice that is lost by the N10 generation, indicating there is likely a strong modifier on the C57BL/6 background. F2, N1, and N3 mice lacking Nr2c1 expression show loss of blue and green opsin expression in the central retina. Immunohistochemistry and ultrastructural results showed morphological and molecular changes in the mutant cone and horizontal cells as well as with disorganization within the outer plexiform layer.
Our results indicate that Nr2c1 functions in the generation of early retinal cone and ganglion cell types and, the specification of synaptic connections within the retina. The abnormalities of the inner retina in Nr2c1-/- animals could result from improper signaling and improper or missing synaptic connections. Our results demonstrate that Nr2c1 plays a crucial role in establishing retinal organization and may direct patterning of cone opsin expression.
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