Retina, Miscellaneous topics
Stimulus-specific and cell type-specific cascades: emerging principles relating to control of apoptosis in the eye.
Wilson SE
Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA, 98195-6485, USA.
Apoptosis has a critical role in development, homeostasis, wound healing, and the pathophysiology of disease in the organs of multicellular organisms. It has been implicated in these processes in retina, lens, cornea, trabecular meshwork, optic nerve, and the central nervous system pathways that contribute to vision. Considerable interest has been focused on inhibiting apoptosis to control disease and wound healing processes in which programmed cell death is thought to have a critical role. A simplified view led to the search for effective inhibitors of 'the final common pathway for apoptosis'. Recent studies have provided important insights into the modulators that participate in and regulate the apoptosis cascades which are activated in response to cytokines, ionizing radiation, chemotherapeutic agents, growth factor deprivation, and other stimulators of cell death. These studies lead to the inescapable conclusion that the apoptosis pathways are not only stimulus-specific, but also cell-type specific. These observations have important implications related to development of pharmacological strategies for controlling apoptosis-associated disease and apoptosis-initiated wound healing.
Keeping an eye on retinal clocks.
Herzog ED, Block GD
Department of Biology and NSF Center for Biological Timing, University of Virginia, Charlottesville 22903, USA. edh3f@virginia.edu
Circadian pacemakers that drive rhythmicity in retinal function are found in both invertebrates and vertebrates. They have been localized to photoreceptors in molluscs, amphibians, and mammals. Like other circadian pacemakers, they entrain to light, oscillate based on a negative feedback between transcription and translation of clock genes, and control a variety of physiological and behavioral rhythms that often includes rhythmic melatonin production. As a highly organized and accessible tissue, the retina is particularly well suited for the study of the input-output pathways and the mechanism for rhythm generation. Impressive advances can now be expected as researchers apply new molecular techniques toward looking into the eye's clock.
The golden age of retinal cell culture.
Seigel GM
Department of Neurobiology & Anatomy and Center for Visual Science, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. gail_seigel@urmc.rochester.edu
In the late 1950s, the study of retinal cells in vitro was in its infancy. Today, retinal cell and tissue culture is routinely used for studies of cell growth, differentiation, cytotoxicity, gene expression, and cell death. This review discusses the major classifications of retinal cell and tissue culture, including primary cell/explant models, retinoblastoma cell lines, and genetically engineered cell lines. These topics are addressed in an historical perspective, coupled with present-day applications for this continually-developing technology.
Development of the retina.
Malicki J
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
As in other vertebrate species, the zebrafish retina is simpler than other regions of the central nervous system. This relative simplicity along with rapid development, and accessibility to genetic analysis make the zebrafish retina an excellent model system for studies of neurogenesis in the vertebrate CNS. Several genetic screens have led to the isolation of an impressive collection of mutants affecting the retina and the retinotectal projections in zebrafish. A variety of techniques and markers are available to study the isolated mutants. These include several antigen- and transcript-detection methods, retrograde and anterograde labeling of neurons, blastomere transplantations, H3 labeling, and others. As past genetic screens have achieved a rather low level of saturation, the current collection of mutants can only grow in the future. Morphological and behavioral criteria have been successfully applied in zebrafish to search for defects in spinal development. In future genetic screens, progressively more sophisticated screening approaches will make it possible to detect very subtle changes in the retinal development. The remarkable evolutionary conservation of the vertebrate eye provides the basis for using the zebrafish as a model system for the detection and analysis of genetic defects potentially related to human eye disorders. Some of the genetic defects of the zebrafish retina indeed resemble human retinopathies. As the genetic analysis of the vertebrate visual system is far from being complete and new techniques are being introduced at a rapid pace, the zebrafish embryo will become increasingly useful as a model for studies of the vertebrate retina.
Melatonin's role in vertebrate circadian rhythms.
Cassone VM
Department of Biology, Texas A&M University, College Station 77843-3258, USA.
The circadian secretion of melatonin by the pineal gland and retinae is a direct output of circadian oscillators and of the circadian system in many species of vertebrates. This signal affects a broad array of physiological and behavioral processes, making a generalized hypothesis for melatonin function an elusive objective. Still, there are some common features of melatonin function. First, melatonin biosynthesis is always associated with photoreceptors and/or cells that are embryonically derived from photoreceptors. Second, melatonin frequently affects the perception of the photic environment and has as its site of action structures involved in vision. Finally, melatonin affects overt circadian function at least partially via regulation of the hypothalamic suprachiasmatic nucleus (SCN) or its homologues. The mechanisms by which melatonin affects circadian rhythms and other downstream processes are unknown, but they include interaction with a class of membrane-bound receptors that affect intracellular processes through guanosine triphosphate (GTP)-binding protein second messenger systems. Investigation of mechanisms by which melatonin affects its target tissues may unveil basic concepts of neuromodulation, visual system function, and the circadian clock.
The retinal pigment epithelium as a developmental regulator of the neural retina.
Jeffery G
Institute of Ophthalmology, UCL, London, UK. g.jeffery@ucl.ac.uk
Melanin-related agents regulate the development of the mammalian neural retina, because in albinos there are a range of retinal deficits including abnormal connections between the eye and brain, an underdeveloped central retina and a rod deficit. These deficits may arise because gradients of retinal development in the albino are delayed and the retina is abnormally proliferative, but also goes through a subsequent period of excessive cell death. This may be caused by a reduction in ocular DOPA in albinos as this is in the synthetic pathway of melanin and is a known cell cycle regulator.
Localization of potassium channels in the retina.
Pinto LH, Klumpp DJ
Northwestern University, Department of Neurobiology and Physiology, Evanston, IL 60208, USA. larry-pinto@nwu.edu
The functional role of the delayed rectifier potassium channels is reviewed and the specific roles that these channels play in the retina is enumerated in examples using retinal neurons. These channels are contrasted with other types of potassium channels. The reasons why several types of delayed rectifier molecules could be expected to be expressed in a single neuron, and specific examples of retinal neurons that would be expected to express several of these molecules are given. The families of delayed rectifier potassium channels are explained and their transmembrane topology is related to their functional characteristics. The approaches to the localization of these channels are given and these methods (in situ hybridization, immunohistochemistry and RT-PCR) are compared and contrasted with examples from retinal neurons. This is followed by specific technical hints for applying these methods to the retina. The localization of the 6 transmembrane domain delayed rectifier channels of the Kv1, Kv2, Kv3 and Kv4 families is given for the retina, the retinal pigment epithelium and the optic nerve. An explanation for why the ionic currents recorded from a cell may not represent accurately the sum of the currents of the ion channels normally expressed in that cell is followed by an example of the assignment of the currents recorded from a retinal neuron to a specific ion channel. The future directions of this type of investigation appear to be to understand the relationship between clustered ion channel molecules of a given type with the function of the subset of the retinal neuron in which this type of ion channel is clustered, to understand the mechanism for the clustering, and to understand the mechanism for the localization of ion channel molecules to one region of the cell i.e. the polarization of the expression of these molecules in retinal neurons.
Ontogeny of the primate fovea: a central issue in retinal development.
Provis JM, Diaz CM, Dreher B
Department of Anatomy and Histology, University of Sydney, Australia. jprovis@anatomy.usyd.edu.au
The formation of the primate fovea has fascinated a substantial number of histologists, pathologists, ophthalmologists and physiologists for more than a century. In this article, using data from the literature as well as our own observations, we identify events which we believe are crucial in this process and present a developmental neurobiologist's view of the formation of the primate fovea. The fovea is a region of the retina specialized for diurnal, high acuity functions which require a high spatial density of cone photoreceptors as well as a large number of inner retinal cells in order to establish the distinct retinofugal pathways (ganglion cell axons) receiving from individual cones in the foveal cone mosaic. A unique feature of the fovea is the displacement of cells connected to the foveal cones onto the rim of the fovea. It is generally believed that this displacement counteracts the problems caused by the scattering of the incoming light by cells and blood vessels of the inner retina. We believe that one of the crucial events in the formation of the primate fovea is the early centripetal migration of photoreceptors towards the central area (centripetal displacement). This process, initiated early in development, continues throughout intrauterine life until some months or years postnatal. We propose that the displacement of cells from the inner layers is related to the earlier developmental accumulation of photoreceptors and inner retinal cells centrally. This, we propose, leads to metabolic "starvation" of the inner retina, resulting from the complete absence of retinal vessels from the vicinity of the incipient fovea. It is suggested that these factors in turn trigger centrifugal displacement of inner retinal cells towards the encroaching perifoveal capillary network and lead to the formation of the foveal depression.
Retinal protein kinase C.
Wood JP, McCord RJ, Osborne NN
Nuffield Laboratory of Ophthalmology, University of Oxford, U.K.
The protein kinase C (PKC) family of serine/threonine kinase isoenzymes are universally expressed in vertebrate tissues where they control vital cellular functioning. PKC comprises twelve currently identified mammalian isoenzymes, described in three distinct groups according to their need for different effector stimulation. Immunological localisation studies in various vertebrate retinas have indicated the presence, so far, of eight of the PKC subspecies, each with a unique cellular distribution in this tissue. Use of these immunological probing techniques with antibodies raised to the individual PKC family members by immunohistochemistry and western blotting, along with biochemical tools such as the potent activators, the tumour-promoting phorbol esters can hopefully lead to elucidation of the roles of these enzymes in the neural retina. Research work to date has pinpointed a number of roles for PKC in this tissue including control of dopamine release, modulation of glutamate receptor function (probably by a process of direct receptor phosphorylation), phosphorylatory modulation of GABAC-receptor function, an involvement in the retinal ischaemic cascade process (the relevance of which is unknown as yet), involvement in control of cytoskeletal interactions by cytoskeletal element-kinase action and feedback control of enzymes involved in the process of inositol phosphate signalling. PKC has been shown to have an important regulatory role in the process of phototransduction: many of the enzymes and proteins making up the phototransduction cascade act as in vitro and in vivo substrates for PKC-dependent phosphorylation and can have their normal function modified in this way. Also, PKC has been implicated in the control of spinule formation in the retina, a process involved in retinal synaptic plasticity and functioning. All of this work has been described, herein. Collation and utilisation of knowledge of all of the work described here may help us to determine the exact roles for individual isoenzymes in the retina. This in turn may help us to understand and further to prevent pathological conditions leading to inappropriate retinal functioning and possible blindness. Furthermore, understanding the roles of PKC in the neural retina may lead us to vital clues in the understanding of the functioning of this important group of enzymes in the nervous system as a whole and eventually to the prevention of many major neuropathological disorders.
Nitric oxide: a review of its role in retinal function and disease.
Goldstein IM, Ostwald P, Roth S
Department of Anesthesia and Critical Care, University of Chicago, IL 60637, USA.
Nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide from L-arginine, exists in three major isoforms, neuronal, endothelial, and immunologic. Neuronal and endothelial isoforms are constitutively expressed, and require calcium for activation. Both of these isoforms can be induced (i.e., new protein synthesis occurs) under appropriate conditions. The immunologic isoform is not constitutively expressed, and requires induction usually by immunologic activation; calcium is not necessary for its activation. Neuronal and immunologic NOS have been detected in the retina. Neuronal NOS may be responsible for producing nitric oxide in photoreceptors and bipolar cells. Nitric oxide stimulates guanylate cyclase of photoreceptor rod cells and increases calcium channel currents. In the retina of cats, NOS inhibition impairs phototransduction as assessed by the electroretinogram. Inducible nitric oxide synthase, found in Muller cells and in retinal pigment epithelium, may be involved in normal phagocytosis of the retinal outer segment, in infectious and ischemic processes, and in the pathogenesis of diabetic retinopathy. Nitric oxide contributes to basal tone in the retinal circulation. To date, findings are conflicting with respect to its role in retinal autoregulation. During glucose and oxygen deprivation, nitric oxide may increase blood flow and prevent platelet aggregation, but it may also mediate the toxic effects of excitatory amino acid release. This reactive, short-lived gas is involved in diverse processes within the retina, and its significance continues to be actively studied.
Spatiotemporal gradients of cell genesis in the primate retina.
Rapaport DH, Rakic P, LaVail MM
Department of Surgery, University of California, San Diego, School of Medicine, La Jolla 92093-0604, USA.
A cardinal event in the development of all brain structures is the time at which progenitor cells leave the cell cycle and begin to differentiate. We examined cell genesis in the retina of the macaque monkey (Macaca mulatta) by labeling dividing cells with radioactive thymidine ([3H]TdR) and following their fate at terminal division by virtue of their remaining radiolabeled after a long survival period. A number of distinct patterns of cell genesis were observed. The two tissues generated by the optic vesicle, the retinal pigment epithelium and neuroretina, share closely coincident temporal and spatial patterns of cell genesis, indicating that this process may be controlled by a common mechanism. Although overlapping to varying degrees, a clear sequence of genesis was revealed between specific cell types within the neuroretina: ganglion cells are generated first, followed by horizontal cells, cone photoreceptors, amacrine cells, Muller cells, bipolar cells, and, finally, rod photoreceptors. Retinal ganglion cells of differing soma diameter are born at different times-the smallest cells are generated early, the largest late, suggesting a further refined sequence of the functional classes of monkey retinal ganglion cells (first P gamma, then P beta, last P alpha). In addition, at sites where a homogeneous population of cells are crowded and stacked on top of each other (the foveola and perifovea for cones and ganglion cells, respectively) there is a vitreal-to-scleral intralaminar pattern of [3H]TdR labeled cell placement, which reflects both time of genesis and pattern of movement during foveation. These gradients suggest several scenarios for cell fate specification in the retina, many of which might not be obvious in mammals that develop more quickly and have less specialized retinal structure. Thus, data from the highly specialized and slowly developing macaque retina can help to understand visual development in humans and indicate useful avenues for future experimental studies in other species.
Involvement of non-receptor protein tyrosine kinases in expression of differentiated phenotype by cells of retinal origin.
Moszczynska A, Opas M
Department of Anatomy and Cell Biology, University of Toronto, Ontario, Canada.
Regulation of phenotypic expression in epithelia in general, and of two epithelia of the retina, the neural retina and retinal pigment epithelium in particular, is dependent on interactions with extracellular environment. Extracellular environment may comprise acellular substrata as well as other cells. Non-receptor protein tyrosine kinases are involved in transmembrane transmission of signals from extracellular milieu, via the cytoskeleton to the nucleus. We describe distribution of these kinases in cells of retinal origin and show that two of them, pp125FAK and pp60c-src redistribute intracellularly in a differentiation-dependent manner. Next we discuss roles that adhesion-related non-receptor protein tyrosine kinases might play in phenotypic expression by the retinal epithelia.
Axonal guidance from retina to tectum in embryonic Xenopus.
Chien CB, Harris WA
Department of Biology, University of California, San Diego, La Jolla 92093.
What do retinal muller (glial) cells do for their neuronal 'small siblings'?
Reichenbach A, Stolzenburg JU, Eberhardt W, Chao TI, Dettmer D, Hertz L
Carl Ludwig Institute of Physiology, Leipzig University, Germany.
Muller (radial glial) cells are the predominant glia of the vertebrate retina. They arise, together with rod photoreceptor cells, bipolar cells, and a subset of amacrine cells, from common precursor cells during a late proliferative phase. One Muller cell and a species-specific number of such neurons seem to form a columnar unit within the retinal tissue. In contrast, 'extracolumnar neurons' (ganglion cells, cone photoreceptor cells, horizontal cells, and another subset of amacrine cells) are born and start differentiation before most Muller cells are generated. It may be essential for such neurons to develop metabolic capacities sufficient to support their own survival, whereas late-born ('columnar') neurons seem to depend on a nursing function of their 'sisterly' Muller cell. Thus, out of the cell types within a retinal column it is exclusively the Muller cell that possesses the enzymes for glycogen metabolism. We present evidence that Muller cells express functional insulin receptors. Furthermore, isolated Muller cells rapidly hydrolyse glycogen when they are exposed to an elevated extracellular K+ ion concentration, a signal that is involved in the regulation of neuronal-glial metabolic cooperation in the brain. Muller cells are also thought to be essential for rapid and effective retinal K+ homeostasis. We present patch-clamp measurements on Muller cells of various vertebrate species that all demonstrate inwardly rectifying K+ channels; this type of channel is well-suited to mediate spatial buffering currents. A mathematical model is presented that allows estimation of Muller cell-mediated K+ currents. A simulation analysis shows that these currents greatly limit lateral spread of excitation beyond the borders of light-stimulated retinal columns, and thus help to maintain visual acuity.
Biological clocks in the retina: cellular mechanisms of biological timekeeping.
Block GD, Khalsa SB, McMahon DG, Michel S, Guesz M
Department of Biology, University of Virginia, Charlottesville 22901.
Plasticity and differentiation of retinal precursor cells.
Adler R
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Histogenesis of the avian retina in reaggregation culture: from dissociated cells to laminar neuronal networks.
Layer PG, Willbold E
Max-Planck-Institut fur Entwicklungsbiologie, Tubingen, Germany.
Positive and negative signaling mechanisms in the regulation of photoreceptor induction in the developing Drosophila retina. Review.
Yamamoto D
Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan.
An ommatidium of a Drosophila compound eye contains eight photoreceptor cells, R1-R8. The fates of the photoreceptors are determined exclusively by inductive interactions between neuronal precursors in the cell cluster from which the ommatidium is formed. R7 induction has been extensively analysed at the molecular level. Activation of a membrane receptor tyrosine kinase (Sevenless) in the R7 precursor by a ligand (Bride of sevenless) present on the surface of R8 triggers a transduction cascade mediated by Ras, establishing the R7 fate of this cell. Other Sev-expressing cells are prevented from taking on the R7 fate by several different mechanisms. Pokkuri-mediated repression represents one such regulatory mechanism. The positive and negative signaling pathways operating in the fate determination of other photoreceptor cells are also discussed.
Melatonin in vertebrate retina: biosynthesis, receptors and functions.
Zawilska JB
Department of Pharmacodynamics, Medical Academy, Lodz, Poland.
The present review primarily summarizes the cellular and molecular biology of MEL synthesis by the vertebrate retina, and the nature of MEL signal generated in this tissue. Additionally, the current status of retinal MEL receptors as well as physiological roles of this indoleamine within the eye are discussed.
Properties and function of the ocular melanin--a photobiophysical view.
Sarna T
Department of Biophysics, Jagiellonian University, Krakow, Poland.
This paper reviews the biosynthesis and physicochemical properties of the ocular melanin. Age-related changes of melanin granules and the corresponding formation of lipofuscin pigments in the retinal pigment epithelium (RPE) are also described. Adverse photoreactions of the eye and, in particular, light-induced damage to the RPE-retina are reviewed in relation to the ocular pigmentation. A hypothesis on the photoprotective role of the RPE melanin is presented that is based on the ability of the cellular melanin to bind redoxactive metal ions. Since bound-to-melanin metal ions are expected to be less damaging to the pigment cells, it is proposed that sequestration of heavy metal ions by the RPE melanin is an efficient detoxifying mechanism. It is postulated that oxidative degradation of RPE melanin may lower its metal-binding capability and decrease its anti-oxidant efficiency. Cellular and environmental factors that may contribute to possible oxidative damage of the RPE melanin are discussed in connection with the etiology of age-related macular degeneration.
Na+, K(+)-ATPase isoforms in the retina.
Schneider B
Department of Pathology, University of Texas Health Science Center, San Antonio 78284.
Regulatory mechanisms in melatonin biosynthesis in retina.
Zawilska JB, Nowak JZ
Department of Pharmacodynamics, Medical University, Lodz, Poland.
The vertebrate retina produces melatonin in a light-dependent rhythmic fashion, synchronized with, but independent from the rhythm of the hormone formation in the pineal gland. This review summarizes the current status of our knowledge on regulatory mechanisms involved in controlling the retinal melatonin biosynthesis. Special emphasis is given to the role and mode of action of dopamine and GABA, two established retinal neurotransmitters, as well as that of second messengers (cyclic AMP, calcium ions). Comparisons are made between lower vertebrates and mammals.
Rhythmic regulation of retinal melatonin: metabolic pathways, neurochemical mechanisms, and the ocular circadian clock.
Cahill GM, Grace MS, Besharse JC
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66103.
1. Current knowledge of the mechanisms of circadian and photic regulation of retinal melatonin in vertebrates is reviewed, with a focus on recent progress and unanswered questions. 2. Retinal melatonin synthesis is elevated at night, as a result of acute suppression by light and rhythmic regulation by a circadian oscillator, or clock, which has been localized to the eye in some species. 3. The development of suitable in vitro retinal preparations, particularly the eyecup from the African clawed frog, Xenopus laevis, has enabled identification of neural, cellular, and molecular mechanisms of retinal melatonin regulation. 4. Recent findings indicate that retinal melatonin levels can be regulated at multiple points in indoleamine metabolic pathways, including synthesis and availability of the precursor serotonin, activity of the enzyme serotonin N-acetyltransferase, and a novel pathway for degradation of melatonin within the retina. 5. Retinal dopamine appears to act through D2 receptors as a signal for light in this system, both in the acute suppression of melatonin synthesis and in the entrainment of the ocular circadian oscillator. 6. A recently developed in vitro system that enables high-resolution measurement of retinal circadian rhythmicity for mechanistic analysis of the circadian oscillator is described, along with preliminary results that suggest its potential for elucidating general circadian mechanisms. 7. A model describing hypothesized interactions among circadian, neurochemical, and cellular mechanisms in regulation of retinal melatonin is presented.
The visual input stage of the mammalian circadian pacemaking system: II. The effect of light and drugs on retinal function.
Terman M, Reme CE, Wirz-Justice A
Columbia University, New York, New York.
Acute light pulses as well as long-term light exposure may not only modulate photoreceptive properties, but also induce reversible or irreversible damage to the retina, depending on exposure conditions. Illuminance levels in laboratory animal colonies and manipulations of lighting regimens in circadian rhythm research can threaten retinal structure and physiology, and may therefore modify zeitgeber input to the central circadian system. Given the opportunity to escape light at any time, the nocturnal rat self-selects a seasonally varying "naturalistic skeleton photoperiod" that protects the eyes from potential damage by nonphysiological light exposures. Both rod rod-segment disk shedding and behavioral circadian phase shifts are elicited by low levels of twilight stimulation. From this vantage point, we hypothesize that certain basic properties of circadian rhythms (e.g., Aschoff's rule and splitting) may reflect modulation of retinal physiology by light. Pharmacological manipulations with or without the addition of lighting strategies have been used to analyze the neurochemistry of circadian timekeeping. Drug modulation of light input at the level of the retina may add to or interact with direct drug modulation of the central circadian pacemaking system.