An evolutionarily restricted role for purinergic signalling in the maintenance of retinal stem cells

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During embryogenesis the eye is formed by a highly organized and stereotyped pattern of events, in which retinal progenitor cells divide (proliferate) many times before exiting the cell cycle and forming the different neuronal cell types of the adult retina in a process called differentiation. Once formed, the mammalian eye is thought to be incapable of regeneration. Thus, any loss of retinal cells, including the light-sensitive photoreceptors, either by disease or injury during life is permanent. In contrast, the eye of lower vertebrates, such as fish and frogs, continues to grow throughout the life of the animal. New retinal neurons, including photoreceptors, are produced by the proliferation of a population of stem cells that reside in a region called the ciliary marginal zone (CMZ), at the very periphery of the retina. Over the past decade, there has been significant interest in the possibility of retinal repair in humans following the discovery of a population of cells within the ciliary epithelium (CE), found within the ciliary body of the mammalian eye, a region analogous to the lower vertebrate CMZ. These cells exhibit a number of stem cell-like properties, although it is not yet clear if these cells can go on to form all the cell types of the retina. More importantly, these cells only proliferate when cultured in a dish - they are dormant in the eye itself. This raises the question of whether these cells represent a population of stem cells that are similar to those found in frogs and fish but that have lost the capacity for proliferation and repair during evolution. Furthermore, it is conceivable that these cells could be reactivated to generate new retinal neurons. The mechanisms that regulate both the proliferation of the stem cells in the lower vertebrate and the apparent dormancy of this stem cell-like population in mammals are poorly understood. Recently, one signalling pathway, called purinergic signalling, has been shown to be essential for turning on a number of genes required for eye formation. We have also shown that this signalling mechanism is very important for controlling the proliferation of retinal progenitor cells in the early stages of eye development in the embryo. Here, we aim to determine whether or not purinergic signalling represents a fundamental regulatory mechanism that controls the proliferation of retinal stem cells at the ciliary margin. Moreover, we wish to determine whether or not this signalling system has become lost or restricted during evolution and so provide an explanation for why the stem cells of the mammalian CE no longer proliferate. We have already found that purinergic signalling is involved in the proliferation of mammalian retinal stem cells in the culture dish. We have also found that a particular type of receptor that is critical for purinergic-mediated proliferation elsewhere in the brain is not present in the mammalian CE, but is found in these cells when they are cultured in the dish. This means it may be possible to induce the normally dormant stem cells of the mammalian eye to proliferate and form new retinal neurons in the eye. Therefore, we aim to firstly examine the role of purinergic signalling in controlling retinal stem cell proliferation both in the adult eye and in the culture dish. We will also determine the downstream pathway of purinergic signalling that leads to this proliferation. We will compare evolutionarily distinct species to examine the role of purinergic signalling in the retina of these animals and finally we will determine whether or not it is possible to reactivate the stem cells of the mammalian CE by purinergic signalling. Although only theoretical at this point, it is possible that the last objective may provide information for the repair of the retina damaged through disease or injury.