Retinal cell survival and cell death

Understanding the ways in which retinal cells develop is very important for providing therapies for diseases that lead to retinal cell death. Use of growth factors to promote cell survival, use of transplanted retinal cells as replacement therapy, and even use of retinal stem cells all require a knowledge of pathways that regulate retinal cell phenotypes.

The most common forms of blindness occur through the death of retinal ganglion cells or photoreceptors. Loss of ganglion cells is the defining characteristic of glaucoma, which remains one of the leading causes of blindness in adults (Quigley et al., 1995). Loss of photoreceptors can involve rods, as in retinitis pigmentosa; or cones, as in macular degeneration; or both, as in rod-cone dystrophies and various syndromes.

A major risk factor for glaucoma is elevated intraocular pressure, which is thought to cause mechanical deformation as the ganglion cells axons leave the eye. This deformation may prevent the retrograde transport of neurotrophic factors. Based on developmental studies showing that brain derived neurotrophic factor (BDNF) is a vital neurotrophic factor for ganglion cells, it has been suggested that BDNF, or agents that mimic BDNF at later points in its pathway of action, might have therapeutic benefit. A second major cause of ganglion cell death in glaucoma is thought to be excitotoxic injury caused by excess glutamate. This might occur as a result of ischemic damage from elevated intraocular pressure or from other retinal defects in cases where pressure seems normal. Excess glutamate has been measured in glaucomatous eyes, and experimental application of glutamate can certainly induce ganglion cell death (Dreyer et al., 1996; Otori et al., 1998). One mechanism that might account for abnormal glutamate metabolism is abnormal uptake or handling by Müller glial cells (Kawasaki et al., 2000). Although glaucomatous eyes do appear to have lower levels of the Müller cell glutamate transporter, it has yet to be shown that this is a primary cause of the disease. Defects at other steps in the glutamate pathway, including glutamine synthetase and glutamine transporters, are also candidates for causing glaucoma. Since several of these molecules show regulation by extrinsic molecules such as corticosteroids, changes in their function could arise from a number of causes. The differences between normal and diseased retinas may initially be very slight. In addition to defects in specific molecules, overall developmental differences that, for example, alter the relative numbers or spacing of ganglion cells and Müller glial cells could influence the tissue's ability to metabolize glutamate.

Retinitis pigmentosa (RP) is an inherited condition in which loss of rod photoreceptors leads to loss of night vision and, later, deleterious secondary changes in cone photore-ceptors (Berson, 1993). A wide array of genes have been identified as causing RP including most of those specific to the phototransduction cascade. Some are loss of function, such as mutations in the cGMP phosphodiesterase; some are structural, such as mutations in the rod outer segment protein peripherin; and still others are "metabolic," such as mutations in the visual pigment protein opsin that seem to clog up the Golgi apparatus of the cell. Mutations in the CRX transcription factor gene can cause loss of rods, and later of cones as well (Freund et al., 1997). Thus, many of the molecules that are thought of as developmental regulators may also play a role in later disease. Trophic factors are thought to play an ongoing role in rod photoreceptor survival. In mouse and rat models of RP, it has been shown that some of the same trophic factors important in rod development and survival can prevent cell death for extended periods (LaVail et al., 1998). Interestingly, one of the factors that helps is CNTF, a factor that can completely block rod formation during development. Such a difference emphasizes that the same molecule can have very different functions at different stages of development.

Only a few clearly inherited forms of macular degeneration (MD) have been described. MD is generally much later in onset and can probably result from many different initial causes (Stone et al., 2001). Most vision loss in MD is caused by rapid proliferation of blood vessels between the RPE and the photoreceptor layer of the retina. This is thought to occur as a secondary consequence of changes in the RPE layer, the photoreceptor layer, or both. It may turn out that the majority of cases of MD are due to defects in the RPE layer. As expected for such a late-onset disease, most forms of MD do not show clear patterns of inheritance. This is probably due to the influence of multiple genes. The best-studied examples of gene mutations that cause MD suggest that abnormal handling of retinoid metabolism in the visual cycle can lead to deposits that cause cone photoreceptor death. It remains to be seen whether mutations in transcription factor genes, such as the homologs of CRX, can also cause specific cone diseases.

One of the therapies under investigation for photorecep-tor degenerative disease is transplantation or cell replacement. For this to be effective, it is essential to know how to treat tissue so that photoreceptors survive and remain functional. We still need to know much more about the factors regulating formation of photoreceptors, particularly those regulating outer segment development. With the increased interest in and potential of stem cell therapies, it is essential that we understand the nature and sequence of factors necessary to turn a cell from a multipotential stem cell or progenitor into the desired phenotype of photoreceptor.

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