tretinoin and Retinitis-Pigmentosa

The SF3B4 gene encodes a highly conserved protein that plays a critical role in mRNA splicing. Mutations in this gene are known to cause Nager syndrome, a rare craniofacial disorder. Although SF3B4 expression is detected in the optic vesicle before it is detected in the limb and somite, the role of SF3B4 in the eye is not well understood. This study investigated the function of sf3b4 in the retina by performing transcriptome profiles, immunostaining, and behavioral analysis of sf3b4

Topics: Animals; Mutation; Retinitis Pigmentosa; RNA Splicing Factors; Spliceosomes; Tretinoin; Zebrafish

Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this interferes with visual perception is unknown. Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice. In vivo Ca

Topics: Animals; Disease Models, Animal; Mice; Retinal Degeneration; Retinal Ganglion Cells; Retinitis Pigmentosa; Tretinoin

Retinitis Pigmentosa (RP) is a progressive, debilitating visual disorder caused by mutations in a diverse set of genes. In both humans with RP and mouse models of RP, rod photoreceptor dysfunction leads to loss of night vision, and is followed by secondary cone photoreceptor dysfunction and degeneration, leading to loss of daylight color vision. A strategy to prevent secondary cone death could provide a general RP therapy to preserve daylight color vision regardless of the underlying mutation. In mouse models of RP, cones in the peripheral retina survive long-term, despite complete rod loss. The mechanism for such peripheral cone survival had not been explored. Here, we found that active retinoic acid (RA) signaling in peripheral Muller glia is necessary for the abnormally long survival of these peripheral cones. RA depletion by conditional knockout of RA synthesis enzymes, or overexpression of an RA degradation enzyme, abrogated the extended survival of peripheral cones. Conversely, constitutive activation of RA signaling in the central retina promoted long-term cone survival. These results indicate that RA signaling mediates the prolonged peripheral cone survival in the rd1 mouse model of retinal degeneration, and provide a basis for a generic strategy for cone survival in the many diseases that lead to loss of cone-mediated vision.

Topics: Animals; Color Vision; Disease Models, Animal; Mice; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinitis Pigmentosa; Tretinoin

Light responses are initiated in photoreceptors, processed by interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information to the brain. Retinitis pigmentosa (RP) is a blinding disease caused by photoreceptor degeneration, depriving downstream neurons of light-sensitive input. Photoreceptor degeneration also triggers hyperactive firing of RGCs, obscuring light responses initiated by surviving photoreceptors. Here we show that retinoic acid (RA), signaling through its receptor (RAR), is the trigger for hyperactivity. A genetically encoded reporter shows elevated RAR signaling in degenerated retinas from murine RP models. Enhancing RAR signaling in healthy retinas mimics the pathophysiology of degenerating retinas. Drug inhibition of RAR reduces hyperactivity in degenerating retinas and unmasks light responses in RGCs. Gene therapy inhibition of RAR increases innate and learned light-elicited behaviors in vision-impaired mice. Identification of RAR as the trigger for hyperactivity presents a degeneration-dependent therapeutic target for enhancing low vision in RP and other blinding disorders.

Topics: Animals; Cell Membrane Permeability; Disease Models, Animal; Electroencephalography; Genetic Therapy; HEK293 Cells; Humans; Mice; Patch-Clamp Techniques; Photosensitivity Disorders; Rats; Receptors, Retinoic Acid; Retinal Degeneration; Retinal Ganglion Cells; Retinitis Pigmentosa; Tretinoin; Vision, Ocular

Transgenic mice expressing a dominant mutation in the gene for the phototransduction molecule rhodopsin undergo retinal degeneration similar to that experienced by patients with the retinal degenerative disease, retinitis pigmentosa (RP). Although the mutation is thought to cause photoreceptor degeneration in a cell-autonomous manner, the fact that rod photoreceptor degeneration is slowed in chimeric wild-type/mutant mice suggests that cellular interactions are also important for maintaining photoreceptor survival. To more fully characterize the nature of the cellular interactions important for rod degeneration in the RP mutant mice, we have used an in vitro approach. We found that when the retinas of the transgenic mice were isolated from the pigmented epithelium and cultured as explants, the rod photoreceptors underwent selective degeneration with a similar time course to that observed in vivo. This selective rod degeneration also occurred when the cells were dissociated and cultured as monolayers. These data indicate that the mutant rod photoreceptors degenerate when removed from their normal cellular relationships and without contact with the pigmented epithelium, thus confirming the relative cell autonomy of the mutant phenotype. We next tested whether normal retinal cells could rescue the mutant photoreceptors in a coculture paradigm. Coculture of transgenic mouse with wild-type mouse or rat retinal cells significantly enhanced transgenic rod photoreceptor survival; this survival-promoting activity was diffusible through a filter, was heat labile, and not present in transgenic retinal cells. Several peptide growth factors known to be present in the retina were tested as the potential survival-promoting molecule responsible for the effects of the conditioned medium; however, none of them promoted survival of the photoreceptors expressing the Pro23His mutant rhodopsin. Nevertheless, we were able to demonstrate that the mutant photoreceptors could be rescued by an antagonist to a retinoic acid receptor, suggesting that the endogeneous survival-promoting activity may function through this pathway. These data thus confirm and extend the findings of previous work that local trophic interactions are important in regulating rod photoreceptor degeneration in retinitis pigmentosa. A diffusible factor found in normal but not transgenic retinal cells has a protective effect on the survival of rod photoreceptors from Pro23His mutant rhodopsin mice.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Brain-Derived Neurotrophic Factor; Cell Survival; Cells, Cultured; Ciliary Neurotrophic Factor; Culture Media, Conditioned; Female; Fibroblast Growth Factor 2; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutagenesis; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; Tretinoin

Patients with retinitis pigmentosa have been suggested to benefit from treatment with moderate doses of retinyl palmitate. Retinyl palmitate is not an active retinoid in itself but is metabolised to active components in the body. To find out which metabolites of retinyl palmitate were formed and at which concentrations, we measured the concentrations of retinol, retinyl palmitate, retinoic acids and tocopherol in serum of patients treated with oral retinyl palmitate for retinitis pigmentosa.. Nine male patients and one female diagnosed as having retinitis pigmentosa after a complete ophthalmological examination including a full-field electroretinogram were given vitamin A at their own request as one daily morning dose of 16600 IU vitamin A. Blood samples were obtained before and after > 2 weeks of treatment. The concentrations of retinoids and tocopherol were measured with established methods.. The patients were not deficient in vitamin A or vitamin E as judged from the serum vitamin concentrations. Treatment with retinyl palmitate significantly increased the serum concentration of retinyl palmitate and of 13-cis-retinoic acid but not of retinol, tocopherol or all-trans-retinoic acid.. Neither retinyl palmitate nor 13-cis-retinoic acid, are known to be biologically active. However, 13-cis-retinoic acid can isomerise to the active vitamin A derivative, all-trans-retinoic acid. It is suggested that patients may be treated with a small dose of 13-cis-retinoic acid instead, to avoid the relatively long metabolic detour from retinyl palmitate.

Topics: Administration, Oral; Adult; Aged; Anticarcinogenic Agents; Chromatography, High Pressure Liquid; Diterpenes; Electroretinography; Female; Humans; Male; Middle Aged; Retinitis Pigmentosa; Retinoids; Retinyl Esters; Tretinoin; Vitamin A; Vitamin E