Abstract
Central nervous system including brain and retina is composed of appropriate number and subtypes of neurons derived from neural progenitor cells. However, our understanding of the proliferation and differentiation of neural progenitor cells is limited. COUP-TFI and -TFII genes, encoding two nuclear receptors, are associated with neurodevelopmental disease and heart defects respectively. Seven-up, the homologous gene of COUP-TF gene in Drosophila, is expressed and required in photoreceptor cell precursors. We observed that along dorso-ventral axis, COUP-TFI and -TFII genes are differentially expressed in mouse retinal stem cells. Minor defects in the eye are generated in either COUP-TFI or -TFII single gene knockout mouse with RXCre. Interestingly, loss of both genes in the retinal stem cells leads to failed differentiation of photoreceptors and thinner retina. The reduced bipolar cells, amacrine cells, horizontal cells, and ganglionic cells are also displayed in the double mutant retina. In addition, the development of Muller cells is repressed accompanying with fibrosis. Mechanistic studies reveal that COUP-TF genes may regulate the differentiation of photoreceptors through Crx and Nrl genes, and modulate the proliferation of retinal stem cells through P27 and P57 genes. Thus, our study shed new light on the understanding of evolutionarily conserved function of COUP-TF genes in the differentiation of photoreceptor cells.