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The orphan nuclear receptor NR2E3 is a direct transcriptional target of NRL, the key basic motif leucine zipper transcription factor that dictates rod versus cone photoreceptor cell fate in the mammalian retina. The lack of NR2E3 function in humans and in retinal degeneration  rd7  mutant mouse leads to increased S-cones accompanied by rod degeneration, whereas ectopic expression of  Nr2e3  in the cone-only  Nrl −/−   retina generates rod-like cells that do not exhibit any visual function. Using GFP to tag the newborn rods and by 5-bromo-2′-deoxyuridine birthdating, we demonstrate that early-born post-mitotic photoreceptor precursors in the  rd7  retina express cone-specific genes. Transgenic mouse studies in the  rd7  background show that  Nr2e3  when expressed under the control of  Crx  promoter can restore rod photoreceptor function and suppress cone gene expression. Furthermore,  Nr2e3  expression in photoreceptor precursors committed to be rods (driven by the  Nrl  promoter) could completely rescue the retinal phenotype of the  rd7  mice. We conclude that excess of S-cones in the  rd7  retina originate from photoreceptor precursors with a ‘default’ fate and not from proliferation of cones and that  Nr2e3  is required to suppress the expression of S-cone genes during normal rod differentiation. These studies further support the ‘transcriptional dominance’ model of photoreceptor cell fate determination and provide insights into the pathogenesis of retinal disease phenotypes caused by  NR2E3  mutations.

human molecular genetics

Excess cones in the retinal degeneration  rd7  mouse, caused by the loss of function of orphan nuclear receptor  Nr2e3 , originate from early-born photoreceptor precursors