The role of Opsin in Circadian Regulation and Photoreceptor Degeneration.

The eye is the sensory organ that enables us to detect light necessary for image formation. Within the eye the light-sensitive retina contains specialized rod and cone photoreceptor cells. These cells are able to absorb light by means of light-sensitive membrane proteins (rhodopsin and cone-opsins), and translate light energy into an electrochemical signal that is processed and eventually transmitted by neuronal cells to the visual cortex. Light is not only the trigger for vision but it is also necessary to regulate the biological clock. This thesis aims to investigate the role of rhodopsin in both aspects, circadian regulation and photoreceptor degeneration. To study the relationship between rhodopsin and the circadian system we used the blind mole-rat, Spalax ehrenbergi. Important elements of the visual system in this animal have regressed or are completely absent but the retina is fully preserved. Bilateral enucleation has been shown to abolish photoentrainment of the biological clock and we therefore assumed that the photopigments remaining in the rudimentary eye could be involved in the regulation of the circadian system. We cloned and characterized rhodopsin and cone-opsins from the Spalax retina and established that these pigments are functional photoreceptor proteins in vitro and in vivo. We hypothesize therefore that these visual pigments have a function in circadian photoreception. Next to its role in vision and regulation of the circadian system, rhodopsin is also an important factor in maintaining the structural and functional integrity of the photoreceptor cell. To study in vivo the effects of rhodopsin mutations known in humans to cause the ocular disease retinitis pigmentosa and, subsequently, to study the role of opsin in maintaining the structural integrity of the rod photoreceptor cell, we generated rhodopsin knock-in mouse models. Intriguing aspects were discovered which lead to a better understanding of the cellular processes underlying photoreceptor degeneration