An isoform of retinoid-related orphan receptor β directs differentiation of retinal amacrine and horizontal interneurons

Amacrine and horizontal interneurons integrate visual information as it is relayed through the retina from the photoreceptors to the ganglion cells. The early steps that generate these interneuron networks remain unclear. Here we show that a distinct retinoid-related orphan nuclear receptor beta 1 (ROR beta 1) isoform encoded by the retinoid-related orphan nuclear receptor beta gene (Rorb) is critical for both amacrine and horizontal cell differentiation in mice. A fluorescent protein cassette targeted into Rorb revealed RORb1 as a novel marker of immature amacrine and horizontal cells and of undifferentiated, dividing progenitor cells. ROR beta 1-deficient mice lose expression of pancreas-specific transcription factor 1a (Ptf1a) but retain forkhead box n4 factor (Foxn4), two early-acting factors necessary for amacrine and horizontal cell generation. ROR beta 1 and Foxn4 synergistically induce Ptf1a expression, suggesting a central role for ROR beta 1 in a transcriptional hierarchy that directs this interneuron differentiation pathway. Moreover, ectopic ROR beta 1 expression in neonatal retina promotes amacrine cell differentiation.