The implications of rod-dependent cone survival for basic and clinical research.

Many inherited retinal degenerations are characterized by an initial rapid period of rod photoreceptor death. Although we still do not understand the complete pathways leading to execution of apoptosis, their destruction is perhaps not surprising, because in most cases in which the gene mutation has been identified, it involves loss or compromise of function of rod-specific proteins. Therefore, in human retinitis pigmentosa (RP), a heterogeneous family of heritable blinding diseases for which there is currently no cure, many mutations have been identified in genes coding for functional (phototransduction) and structural proteins. Animal models of inherited retinal degeneration show very similar causes. The retinal degeneration (rd) mouse is a naturally occurring mutant strain exhibiting mutations in the gene coding for the b subunit of rod cyclic guanosine monophosphate (cGMP) phosphodiesterase, as is seen in some forms of human RP. In this animal, rod degeneration is rapid and practically complete within 1 month of postnatal age. The retinal degeneration slow (rds) mouse strain exhibits defects in the gene coding for rds/ peripherin, as observed in human RP. Rod degeneration in this case is much slower than in the former mutant, occurring over many months rather than days. Nevertheless, rods eventually die by apoptosis. Many transgenic strains have been prepared in which abnormal rhodopsin genes have been inserted, resembling the different forms of human RP. These include mice, rats, and pigs, and rod cells invariably degenerate and die as a result of the mutation. Yet, in all cases for which data are available, one observation of paramount importance has no current explanation: Subsequent to the initial phase of rod cell loss there is a second wave of cone cell death. Examination of rod and cone dysfunction in 18 different human rhodopsin mutations has demonstrated that cone loss is spatially and temporally correlated with that of rods. The rd mouse exhibits delayed cone degeneration after rod death. Transgenic mice in which rod photoreceptors are ablated with toxic transgenes show secondary cone defects. Transgenic pigs containing mutant rhodopsin genes reveal cone destruction paralleling that observed in rods. Why should these cells, which for the most part are not the population harboring the defective gene (but see later discussion) also degenerate? The answer to this question is of fundamental importance to vision research biologists and clinicians. For the biologist it raises the possibility of rod–cone interactions playing a vital role in coordinating photoreceptor development and survival. For clinicians it is the secondary cone death in RP that accounts for the most debilitating aspect of vision loss. Whereas rod breakdown results in night blindness and restriction of the visual field, cone destruction leads to disappearance of central vision and renders the affected person unable to distinguish colors or details. It is easy to imagine one of at least two non–mutually exclusive scenarios to account for this delayed cone loss. In the first, rod breakdown would adversely affect neighboring cones through nonspecific environmental influences. The progressive disintegration of the surrounding far more numerous rods may leave the cone outer segments exposed, say, to toxic concentrations of neurotransmitters. Although rods die by apoptosis, which normally avoids release of potentially toxic cellular metabolites that would create problems of poisoning or inflammation and therefore prevents extension of cellular breakdown to surrounding regions of tissues, it seems nevertheless possible that degeneration of the abundant rods (;20 times more numerous than cones in many mammalian species, including man) could exert adverse effects on the adjacent cones. However if rods were releasing general toxic biproducts, other nearby cell types, such as the immediately postsynaptic partners of photoreceptors, the bipolar cells, would be expected to die as well. Although there are some modifications of inner retinal neurons after photoreceptor loss, they do not undergo widespread death. Furthermore, each cone is individually surrounded by an insoluble glycocalyx that forms a privileged structural microdomain linking each cone to a retinal pigment epithelial (RPE) cell. A second explanation, which if true could have far-reaching implications, is that rods produce some kind of signal that is essential for maintaining cone viability, so that the disappearance of rods for whatever reason would deprive the cones of this signal and trigger their degeneration. This idea may seem far fetched, but both circumstantial evidence and recent experimental findings suggest that not only do such rod–cone interactions exist, but also that we can intervene to limit or prevent secondary cone death. Although both types are involved in transducing light energy into electrical signals relayed to the secondand thirdorder retinal neurons, many aspects of rod and cone biology differ. In most species cone cells are among the first retinal cell types to leave the cell cycle, whereas rods are generally among the last to do so. Evidence suggests cones may organize the photoreceptor mosaic through inducing differentiation of neighboring uncommitted precursors. But other data indiFrom Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, EMI 99-18 Institut National de la Santé et de la Recherche Médicale, Universite Louis Pasteur, Hôpitaux Universitaires de Strasbourg, France. Submitted for publication June 1, 1999; revised July 13, 1999; accepted July 15, 1999. Commercial relationships policy: N. Corresponding author: David C. Hicks, Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, EMI 99-18 Institut National de la Santé et de la Recherche Médicale, Universite Louis Pasteur, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. E-mail: hicks@neurochem.u-strasbg.fr