Birth and Death in the Retina
Authors: Donald J. Zack
Journal: Neuron (1999)

The retina is a specialized region of the central nervous system that has been extensively studied not only because of its importance in vision but also because of its usefulness as a model system for analysis of brain development, function, and pathology. Developmentally, the retina achieves its beautiful laminated structure through carefully choreographed migration and differentiation of pluripotential progenitor cells. Functionally, the retina carries out not only phototransduction but also the initial stages of visual processing. Phototransduction is mediated by two flavors of photoreceptors, rods and cones. Rods are responsible for vision in low-light conditions, while cones are responsible for color and high-acuity vision. Information processing involves a complex network of cells including rod and cone bipolar, horizontal, amacrine, and ganglion cells (see figure). Although there is increasing evidence of some overlap, for the most part rod and cone pathways to ganglion cells and beyond appear to be largely independent (8Soucy E. Wang Y. Nirenberg S. Nathans J. Meister M. Neuron. 1998; 21: 481-493Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). Pathologically, most forms of retinal disease involve loss of either photoreceptors (retinal degeneration) or ganglion cells (glaucoma and other forms of optic atrophy). Traditionally, retinal development and retinal degeneration have been largely separate subjects studied by different investigators using distinct experimental approaches. Recently, aspects of the two fields have begun to merge. One important uniting theme has been the realization that apoptosis is central to both the “pruning” of cells that takes place during the formation of the retina and the death of cells observed in many forms of retinal disease (1Adler R. Arch. Ophthalmol. 1996; 114: 79-83Crossref PubMed Scopus (79) Google Scholar). Another contributory factor has been the realization that mutations in transcription factors that are important in retinal development can also cause retinal degeneration (3Freund C.L. Gregory-Evans C.Y. Furukawa T. Papaioannou M. Looser J. Ploder L. Bellingham J. Ng D. Herbrick J.-A.S. Duncan A. et al.Cell. 1997; 91: 543-553Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 10Swain P.K. Chen S. Wang Q.L. Affatigato L.M. Coats C.L. Brady K.D. Fishman G.A. Jacobson S.G. Swaroop A. Stone E. et al.Neuron. 1997; 19: 1329-1336Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 6Morrow E.M. Furukawa T. Cepko C.L. Trends Cell Biol. 1998; 8: 353-358Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). The paper by Jacobson and colleagues in this issue of Neuron (2Banin E. Cideciyan A.V. Aleman T.S. Petters R.M. Wong F. Milam A.H. Jacobson S.G. Neuron. 1999; 23 (this issue,): 549-557Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) demonstrates how studies of disease processes can shed new light on basic developmental processes. 2Banin E. Cideciyan A.V. Aleman T.S. Petters R.M. Wong F. Milam A.H. Jacobson S.G. Neuron. 1999; 23 (this issue,): 549-557Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar began their studies intending to use noninvasive electrophysiological recordings (electroretinograms or ERGs) to more fully characterize the retinal degeneration in a transgenic pig model of autosomal-dominant retinitis pigmentosa (RP). RP is a genetically heterogeneous disease in which there is progressive loss of rod photoreceptors, resulting initially in night blindness and loss of mid-peripheral vision. Although the age of onset and severity of the disease is variable, it often first becomes symptomatic during a patient's late teens. During the early stages, cone function is generally normal; in later stages, however, there is often death of cones, resulting in loss of central vision and, all too often, total blindness. Although it is this secondary death of cones that is responsible for most visual morbidity, little is known about the mechanisms by which rod loss leads to cone loss. This is clinically a crucial issue because in our well-lighted society an individual with cones, but no rods, can live an essentially normal life. The pig proline-347-leucine rhodopsin mutant was generated in an effort to develop a model of human retinal degeneration that would overcome some of the disadvantages of the murine transgenic models (7Petters R.M. Alexander C.A. Wells K.D. Collins E.B. Sommers J.R. Blanton M.R. Rojas G. Hao Y. Flowers W.L. Banin E. et al.Nat. Biotechnol. 1997; 15: 965-970Crossref PubMed Scopus (244) Google Scholar). The obvious advantages of the pig model are that the pig eye is larger than the murine eye, is more similar in structure to the human eye, and has a ratio of cones to rods that is higher than in the mouse. This has allowed therapeutic and surgical interventions in the pig model that are quite difficult to carry out in the mouse and is a particular advantage in studies of cone survival. In analyzing ERG recordings from mutant pigs, Jacobson and colleagues made the unexpected finding that even in animals in which there is not yet a detectable decrease in cone function, there is already a readily detectable malfunction in the postsynaptic cells involved in the cone pathway, specifically the hyperpolarizing cells distal to the middle wavelength–sensitive cones. This was a particularly surprising finding because, although prior studies had shown that there are inner retinal abnormalities associated with photoreceptor cell degeneration, these were thought to be secondary to loss of photoreceptors in the involved pathway (5Milam A.H. Li Z.Y. Fariss R.N. Prog. Retinal Eye Res. 1998; 17: 175-205Crossref PubMed Scopus (507) Google Scholar). These new results suggest that there may be abnormalities in the development of retinal networks resulting from alterations of sensory input, cell–cell interactions, or the processes that cause the retinal degeneration itself. Even before the work of 2Banin E. Cideciyan A.V. Aleman T.S. Petters R.M. Wong F. Milam A.H. Jacobson S.G. Neuron. 1999; 23 (this issue,): 549-557Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, there were an increasing number of experiments suggesting that retinal degeneration was not a simple process but was complicated by the involvement of cell–cell interactions and the importance of trophic effects. The field of genetics was one contributor in this controversy. The finding that mutations in rhodopsin could cause a specific photoreceptor cell degeneration initially made sense and seemed simple; in this case, a gene that is specifically expressed in rods is mutated and thereby leads to death of the cells that express the mutated gene. However, it soon became clear that genes that are expressed widely throughout the body can also cause specific photoreceptor cell degeneration. An extreme example of this lack of correlation of expression pattern and clinical phenotype is provided by ABCR, the gene that is responsible for the macular degeneration known as Stargardt disease (see also the Preview by Bok in this issue). Functionally, the primary cell affected in this condition is the cone photoreceptor, although pathologists and clinicians have for a long time thought that the primary defect was in retinal pigment epithelial (RPE) cells. However, it turns out that ABCR is expressed neither in RPE nor in cone cells, but rather is expressed exclusively in the disc membranes of rod outer segments (9Sun H. Nathans J. Nat. Genet. 1997; 17: 15-16Crossref PubMed Scopus (212) Google Scholar). Thus, in Stargardt disease the genetic defect in rod cells apparently affects RPE cells, which in turn affect cone cells. Even the situation with rhodopsin mutations is complex, as demonstrated by the finding of apparent non–cell autonomous cell death. In chimeric animals containing a mixture of wild-type photoreceptors as well as cells that carry a mutant rhodopsin transgene, the wild-type photoreceptors die and they die just as fast as the transgenic cells (4Huang P.C. Gaitan A.E. Hao Y. Petters R.M. Wong F. Proc. Natl. Acad. Sci. USA. 1993; 90: 8484-8488Crossref PubMed Scopus (124) Google Scholar). The 2Banin E. Cideciyan A.V. Aleman T.S. Petters R.M. Wong F. Milam A.H. Jacobson S.G. Neuron. 1999; 23 (this issue,): 549-557Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar paper thus adds complexity to a field that is already complicated. It is in fact one of those important pieces of work that raises more questions than it answers. It will cause investigators in the field to rethink many of their treasured paradigms. As a first step, especially due to complications in the extraction of cellular information from ERG recordings, it will be important to reproduce and extend the findings using similar as well as complementary approaches. Since it is becoming increasingly clear that there are significant differences between vertebrate retinae, it will be important to test whether the observed phenomena are unique to the pig retina or are common to other mammalian, and perhaps also other vertebrate, retinae. Are species in which there is prominent postnatal retinal development more likely to demonstrate these changes? Although data are presented to suggest similar postsynaptic cone pathway changes in the human, it is not totally convincing. If such changes do occur in humans, are there psychophysical and perceptual sequelae of these changes? What are the cellular and molecular mechanisms by which early-onset retinal degenerations affect development? Finally, the results presented raise an additional concern about how successful therapeutic strategies aimed at photoreceptor replacement will be in restoring vision in patients with late-stage retinal degeneration.