Minireview: the role of nuclear receptors in photoreceptor differentiation and disease

Abstract

Rod and cone photoreceptors are specialized sensory cells that mediate vision. Transcriptional controls are critical for the development and long-term survival of photoreceptors; when these controls become ineffective, retinal dysfunction or degenerative disease may result. This review discusses the role of nuclear receptors, a class of ligand-regulated transcription factors, at key stages of photoreceptor life in the mammalian retina. Nuclear receptors with known ligands, such as retinoids or thyroid hormone, together with several orphan receptors without identified physiological ligands, complement other classes of transcription factors in directing the differentiation and functional maintenance of photoreceptors. The potential of nuclear receptors to respond to ligands introduces versatility into the control of photoreceptor development and function and may suggest new opportunities for treatments of photoreceptor disease.

Fig. 1.

Photoreceptor phenotypes caused by nuclear receptor mutations. The mouse retina is represented in a simplified flat surface view to show the patterning of rods (pink), M cones (green), and S cones (blue). A, In wild-type mice, cones express M and S opsins in opposing gradients across the superior-inferior (dorsal-ventral) surface of the retina, as indicated to the left of the retina. Superior regions contain M cones and inferior regions, S cones. In mice, cones in midretinal regions express varying amounts of both opsins, although these are not shown here for simplicity. In wild-type mice, the ratio of rods to cones is 97:3. B, Thrb2^−/− mice deleted for TRβ2 fail to produce M cones, and all cones instead shift to an S opsin identity. Thrb2^−/− mice represent a model of blue monochromatic color blindness. C, Rorb^−/− mice, deleted for RORβ fail to produce rods and instead produce an excess of primitive S cone-like cells. D, Esrrb^−/− mice, deleted for ERRβ, produce rods, M cones, and S cones but progressively lose rods at adult ages and represent a model for rod-selective degeneration.

Fig. 2.

Nuclear receptors and photoreceptor differentiation in mice. Nuclear receptors (genes in blue type) act at several early and later stages of photoreceptor differentiation. In a current model of photoreceptor differentiation, multipotent, proliferative progenitors produce photoreceptor precursors under the control of Otx2 homeodomain factor and other poorly understood factors. These photoreceptor precursors are directed to a rod fate by leucine zipper factor NRL and nuclear receptors RORβ and NR2E3. If the NRL-NR2E3 pathway fails to reach a threshold of activity, the precursor becomes a cone by default. In cones, TRβ2 induces M opsin and suppresses S opsin, depending on thyroid hormone levels and location of the cone on the retina. In the absence of NRL or TRβ2, a photoreceptor precursor differentiates by default as an S cone. Many other factors cooperate to promote photoreceptor differentiation, including transcriptional cofactors, local extracellular signaling factors, and systemic hormonal and vitamin signals. Levels of RA and thyroid hormone can be regulated within the retina by ligand-metabolizing enzymes. Note: 1) Gene locations indicate stages where functions are reported, not necessarily where a gene is first expressed; 2) Expression patterns at early stages are not precisely defined for all genes; some genes may be expressed in dividing progenitor cells and/or early postmitotic cells; 3) Some genes may act at several stages in a cell lineage.

Fig. 3.

Natural and artificial ligands for nuclear receptors in the retina. The examples shown represent the natural ligand for TRβ2 (triiodothyronine) and synthetic agonists for NR2E3 (11a) and ERRβ (DY131).