Rod differentiation factor NRL activates the expression of nuclear receptor NR2E3 to suppress the development of cone photoreceptors.

Neural developmental programs require a high level of coordination between the decision to exit cell cycle and acquisition of cell fate. The Maf-family transcription factor NRL is essential for rod photoreceptor specification in the mammalian retina as its loss of function converts rod precursors to functional cones. Ectopic expression of NRL or a photoreceptor-specific orphan nuclear receptor NR2E3 completely suppresses cone development while concurrently directing the post-mitotic photoreceptor precursors towards rod cell fate. Given that NRL and NR2E3 have overlapping functions and NR2E3 expression is abolished in the Nrl(-/-) retina, we wanted to clarify the distinct roles of NRL and NR2E3 during retinal differentiation. Here, we demonstrate that NRL binds to a sequence element in the Nr2e3 promoter and enhances its activity synergistically with the homeodomain protein CRX. Using transgenic mice, we show that NRL can only partially suppress cone development in the absence of NR2E3. Gene profiling of retinas from transgenic mice that ectopically express NR2E3 or NRL in cone precursors reveals overlapping and unique targets of these two transcription factors. Together with previous reports, our findings establish the hierarchy of transcriptional regulators in determining rod versus cone cell fate in photoreceptor precursors during the development of mammalian retina.