Otx2 RPE-specific functions are necessary for photoreceptor maintenance. M/A, Microphthalmia/anophthalmia Oca, oculocutaneous albinism CSNB, congenital stationary night blindness RP, retinitis pigmentosa. Gene symbols of downregulated (blue) and upregulated (red) genes are indicated in front of corresponding retinopathies. Red portion of chart represents deregulated genes related to five types of retinopathies. Functional clusters identified within each group are shown with gene symbols.

Distribution of downregulated (light blue) and upregulated (light red) genes is shown in the surrounding ring. B, Distribution of deregulated genes according to retinal cell-type specificity and functional clusters: genes exclusively expressed in RPE cells (blue, 34%), in bipolar cells (green, 14%), or not determined or not specific of a cell-type (N.D., brown, 52%). Histograms represent the number of color-coded genes of each category, with statistical significance shown by p value. A, Gene Ontology analysis of deregulated genes. Significant changes between relevant consecutive time points: * p ≤ 0.05 (Student's t test) ** p ≤ 0.01 (Student's t test) *** p ≤ 0.001 (Student's t test).įunctional categorization of genes deregulated after Otx2 ablation. Genes are categorized according to their profile in the time-series gene expression analysis. Histograms represent percentage of mRNA level at each time relative to level on day 0. C, Representative examples of qRT-PCR validation of all classes of deregulated genes after Otx2 sKO in the adult retina. Right, Schematics of kinetic profile for each gene set with the number of downregulated (blue line) and upregulated (red line) genes. Heat map shows the averaged expression relative to day 0 for each time point. Left, Downregulated and upregulated genes were grouped into three gene sets according to their kinetics of variation: early, continuous, and late. B, Clustering of differentially expressed genes after Otx2 sKO. A, Schematic of the sampling for time-series transcriptome analysis. Two waves of gene deregulation are induced after Otx2 sKO in the mature retina. These findings thus provide novel general markers for clinical detection and prevention of neuronal cell death. Importantly, we report a secondary genetic response after Otx2 ablation, which largely precedes apoptosis of photoreceptors, involving inflammation and stress genes. Many direct Otx2 target genes are associated with human retinopathies, emphasizing the significance of the model. We uncover four RPE-specific functions coordinated by Otx2 that underpin the cognate photoreceptor degeneration. We use chromatin immunoprecipitation followed by massive sequencing (ChIP-seq) analysis to identify the molecular network controlled in vivo by Otx2 in RPE cells. In contrast, constitutive Otx2 expression in RPE cells prevents degeneration of photoreceptors in Otx2-ablated retinas. This is confirmed by RPE-specific ablation of Otx2, which results in similar photoreceptor degeneration.

Electroretinography and gene expression analyses suggest a nonautonomous, RPE-dependent origin for photoreceptor degeneration.

Here, we use this model to identify the earliest events after Otx2 ablation. Conditional Otx2 ablation in the adult mouse retina elicits photoreceptor degeneration, providing a new model of late-onset neuronal disease. Despite intense interest in the etiology of these diseases, early molecular actors of late-onset photoreceptor degeneration remain elusive, mostly because of the lack of dedicated models. Frequent in the elderly, photoreceptor loss can originate from primary dysfunction of either cell type. Photoreceptors are specialized neurons of the retina that receive nursing from the adjacent retinal pigment epithelium (RPE).

Otx boys meaning