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In-Jung Kim, Jonathan B Demb, Haewon Byun; Retinoid-related orphan receptorβ regulates the balance of ipsilateral and contralateral ganglion cells in mouse retina. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2591.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cells (RGCs) convey the retinal output to the brain and divide into two groups according to their axonal projections: ipsilaterally-projecting RGCs (ipsi-RGCs) project to the same hemisphere, whereas contralaterally-projecting RGCs (contra-RGCs) cross and project to the opposite hemisphere. The ratio of ipsi-RGCs to contra-RGCs determines the extent of binocular vision, which supports depth perception. Here, we investigated a novel mechanism, mediated by retinoid-related orphan nuclear receptor β (Rorβ), that regulates the balance between ipsi- and contra-RGCs.
Using a gain-of-function approach, we delivered Rorβ DNA into the eyes of the embryonic day 13 (E13) control mouse, via in utero electroporation, and examined retinas at E16 or E18. Using a loss-of-function approach, we studied the Rorβ knock-in mouse, in which the open reading frame of green fluorescent protein replaces the Rorβ1 specific exon (Liu et al., 2013: kindly provided by D. Forrest at NIDDKD). Retinas from control and mutant mice were analyzed at E11-E18. Ipsi-RGCs were visualized with an antibody to Zic2, and contra-RGCs were visualized with antibodies to Brn3a and Isl2. Labeled cells were visualized with confocal microscopy and quantified across 6-9 sections from 3-4 animals.
Overexpression of Rorβ in embryonic retina led to the overproduction of contra-RGCs and underproduction of ipsi-RGCs. Deletion of Rorβ led to the opposite phenotype: delayed differentiation of contra-RGCs and overproduction of ipsi-RGCs. In addition, deletion of Rorβ decreased the level of sonic hedgehog (Shh), which is normally expressed exclusively in contra-RGCs and negatively regulates development of ipsi-RGCs (Sánchez-Arrones et al., 2013). These data suggest that Shh could act as a downstream mediator of Rorβ.
Rorβ regulates the propagation of contra-RGC differentiation and is both necessary and sufficient for generating the balance of ipsi-RGCs to contra-RGCs. Our data show for the first time that disrupting the timing of contra-RGC development alters the relative specification of ipsi- and contra-RGCs. These results reveal a novel molecular mechanism for regulating the ratio of ipsi- to contra-RGCs and thereby establishing healthy binocular vision.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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