The Orphan Nuclear Receptor Nr2e3 Plays Dual Functions In Rod Photoreceptor Differentiation

During retinal development, rod and cone photoreceptors are generated from common pools of neuroepithelial progenitors. Nrl, Crx, and Nr2e3 are the key transcriptional regulators that control rod differentiation. Nr2e3 is a rod photoreceptor specific orphan nuclear receptor. However, the loss of its function results in enhanced S-cones and rod degeneration in both human (ESCS patients) and mice (rd7) retina. Nr2e3 is not detected in the Nrl / retina, which exhibits excess functional S-cones at the expense of rods. Here, we show that, using GFP to tag the newborn rod precursors, some early born rod precursors are transformed into S-opsin-positive cells in the rd7 mouse. On the other hand, forced over-expression of functional Nr2e3 in postmitotic cone precursors induces them to adopt rod pathway at the expense of cone differentiation. However, these new rod-like photoreceptors are not functional, partially due to the lack of rod transducin. The dual functions of Nr2e3 on rod and cone gene regulation are not dependent on Nrl and/or Crx but rely on its expression time and level. Thus, our in vivo studies reveal a critical role of Nr2e3 in rod photoreceptor differentiation during retinal development.