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PubMed1996

Death in a dish: controls of apoptosis within the developing retinal tissue.

Studies of programmed cell death in the developing retina in vitro are currently reviewed. The results of inhibiting protein synthesis in retinal explants indicate two mechanisms of apoptosis. One mechanism depends on the synthesis of positive modulators ('killer proteins'), while a distinct, latent mechanism appears to be continuously blocked by negative modulators. Extracellular modulators of apoptosis include the neurotrophic factors NT-4 and BDNF, while glutamate may have either a positive or a negative modulatory action on apoptosis. Several protein kinases selectively modulate apoptosis in distinct retinal layers. Calcium and nitric oxide were also shown to affect apoptosis in the developing retinal tissue. The protein c-Jun was found associated with apoptosis in various circumstances, while p53 seems to be selectively expressed in some instances of apoptosis. The results indicate that the sensitivity of each retinal cell to apoptosis is controlled by multiple, interactive, cell type- and context-specific mechanisms. Apoptosis in the retina depends on a critical interplay of extracellular signals delivered through neurotrophic factors, neurotransmitters and neuromodulators, several signal transduction pathways, and the expression of a variety of genes.

Animals↗
PubMed2002

Dynamic microtubule-dependent interactions position homotypic neurones in regular monolayered arrays during retinal development.

In the vertebrate retina cell layers support serial processing, while monolayered arrays of homotypic neurones tile each layer to allow parallel processing. How neurones form layers and arrays is still largely unknown. We show that monolayered retinal arrays are dynamic structures based on dendritic interactions between the array cells. The analysis of three developing retinal arrays shows that these become regular as a net of dendritic processes links neighbouring array cells. Molecular or pharmacological perturbations of microtubules within dendrites lead to a stereotyped and reversible disruption of array organization: array cells lose their regular spacing and the arrangement in a monolayer. This leads to a micro-mechanical explanation of how monolayers of regularly spaced 'like-cells' are formed.

Animals↗
PubMed2004

Caspase-3 in postnatal retinal development and degeneration.

PURPOSE: The primary purpose of this study was to evaluate the impact of caspase-3 ablation on photoreceptor degeneration in the rd-1 mouse. Concurrently, the role of caspase-3 in postnatal retinal development was evaluated. Caspase-3 is an important effector caspase that mediates many of the terminal proteolytic events of apoptosis. Its activation has been demonstrated in rodent models of photoreceptor degeneration and its ablation results in exencephaly and neonatal death. METHODS: Retinal morphometry was performed at the light microscopic level in caspase-3 mutant mice from PN0 through PN23, and in rd-1/caspase-3 double mutant mice at PN14, -16, and -18. This was supplemented by terminal dUTP transferase nick end labeling (TUNEL) and immunohistochemical staining for activated caspase-3, rhodopsin, factor VII-related antigen and proliferating cell nuclear antigen (PCNA). RESULTS: Caspase-3-deficient animals display marginal microphthalmia, peripapillary retinal dysplasia, delayed regression of vitreal vasculature, and retarded apoptotic kinetics of the inner nuclear layer. Ablation of caspase-3 provided transient photoreceptor protection in rd-1, but TUNEL-positive rod death proceeded, despite the absence of caspase-3 activation. CONCLUSIONS: In vivo, caspase-3 is not critical for rod photoreceptor development, nor does it play a significant role in mediating pathologic rod death. Peripapillary dysplastic lesions suggest that there is delayed fusion of the optic fissure, and inner nuclear layer abnormalities indicate a cell-specific dependency on the mitochondria-caspase axis during development. The temporal nature of apoptotic retardation in the absence of caspase-3 implies the presence of caspase-independent mechanisms of developmental and pathologic cell death.

Animals↗
PubMed1999

Marked alteration of sterol metabolism and composition without compromising retinal development or function.

PURPOSE: To evaluate the consequences of altering retinal sterol metabolism and composition on the development, histologic organization, and electrophysiological function of the retina, under conditions that mimic the biochemical hallmarks of the Smith-Lemli-Opitz (SLO) syndrome. METHODS: Pregnant Sprague-Dawley rats were fed cholesterol-free chow containing AY9944 (treated group), an inhibitor of 3beta-hydroxysterol delta7-reductase, from gestational day 6 through postnatal day (P)28. Control animals were fed the same chow, but without AY9944. In addition, progeny in the treated group were injected subcutaneously every other day from birth to P28 with an olive oil emulsion containing AY9944; control animals received olive oil emulsion alone. At various postnatal times, tissues from treated and control animals were harvested, and their sterol profiles were analyzed by reversed-phase high-performance liquid chromatography. Companion eyes from animals of both groups were examined histologically at P1. At P28, animals were evaluated by electroretinography; tissues were then harvested for biochemical analysis and companion eyes were subjected to histologic and ultrastructural analyses. RESULTS: Treatment of developing rats with AY9944 caused markedly abnormal accumulation of 7-dehydrosterols and severely reduced cholesterol levels in all tissues examined, relative to control animals. Despite this, treated animals exhibited normal retinal development and had no overt ocular defects or decrease in electroretinographic function, up to P28. CONCLUSIONS: These results were unexpected, given the known biophysical effects of such sterol alterations on membrane properties and the profound dysmorphic and cognitive abnormalities associated with genetic defects in 3beta-hydroxysterol delta7-reductase that have been linked to the SLO syndrome. The results suggest that 7-dehydrosterols can substitute functionally for cholesterol in the retina or perhaps can act synergistically with subthreshold levels of residual cholesterol to allow normal cellular structure and function to be achieved.

Animals↗
PubMed1986

Rhodopsin, 11-cis vitamin A, and interstitial retinol-binding protein (IRBP) during retinal development in normal and rd mutant mice.

Biochemical and immunological techniques were used to determine the emergence of interstitial retinol binding protein (IRBP), rhodopsin, and stored retinyl esters (all-trans and 11-cis) during retinal development in normal and rd mice. IRBP could be demonstrated at embryonic Day 17 (E17), corresponding to an early stage of inner segment development. Although all-trans retinyl esters were present earlier, 11-cis retinyl esters did not appear until postnatal Days 6-7 (P6-P7), corresponding to rod outer segment (ROS) disc formation. Rhodopsin was detected at the same developmental stage. The proportion of 11-cis retinyl esters reached a maximum of 40-50% at P15-P20. Thereafter, the proportion dropped, due to more rapid accumulation of the all-trans isomer. Rhodopsin and IRBP increased in parallel with ROS elongation up to P25, when the ROS had reached their mature lengths. The increases then continued up to P40-P50. In rd (retinal degeneration) mice, IRBP and rhodopsin were identical with the controls until P12, but then dropped as the photoreceptors degenerated. Synthesis and secretion of IRBP in vitro was less than 10% of the controls in rd retinas at P26, when only 4-5% of the photoreceptors survived. The quantities of retinyl esters (mainly stearate and palmitate in the ratio of 6:1, respectively) stored in dark-adapted mouse eyes progressively increased as the animals aged, representing 0.5 mole eq. of the rhodopsin at 8 months. Although retinyl esters (11-cis and all-trans) also accumulated in rd mouse eyes up to P12, little further increase occurred. At P93, the retinyl esters (0.01 nmole X eye-1) were only 4% of the controls at P91. A peak in the proportion of 11-cis isomer occurred at P10-P20, but it averaged only 15% of the total ester and declined to 5% at P93. These findings support the hypothesis that IRBP is synthesized by the rods and cones, and suggest that its synthesis and secretion are initiated when the photoreceptor inner segments start to differentiate. 11-cis Retinoids and rhodopsin do not appear until the outer segments start to form. It is suggested that in the rd mouse the absence of photoreceptors, perhaps coupled with lack of normal interphotoreceptor matrix, leads to a loss in the ability of the pigment epithelium to store retinyl esters.

Animals↗
PubMed2003

Involvement of numb in vertebrate retinal development: evidence for multiple roles of numb in neural differentiation and maturation.

Cell fate specification is regulated in part by lateral inhibition mediated by Notch signaling. Notch signaling is negatively regulated by Numb, an intrinsic factor that regulates cellular competence. In this study we have examined the involvement of Numb in retinal development, which has been shown to be influenced by Notch signaling. In the developing retina, Numb is asymmetrically distributed towards the ventricular and vitreal poles of different cells. Asymmetric localization is evident not only in mitotic cells but in postmitotic ganglion cells as well, suggesting that the subcellular distribution of Numb may play a role after cells have exited the cell cycle. This is supported by the expression of Numb in terminally differentiated neurons in the adult retina. Although Numb is an intrinsic factor, it is observed that its subcellular distribution is influenced by epigenetic cues such that a higher proportion of cells cultured at high density express Numb asymmetrically. A correlation is observed between asymmetric localization and cellular competence; cells in which Numb is asymmetric differentiate more readily in culture than those that express Numb symmetrically. We have identified alternative splice variants in the developing and adult retina that correspond to isoforms that have been shown to regulate proliferation and differentiation. The dynamic temporal expression patterns of alternative splice variants and isoforms suggest that Numb may influence proliferation and differentiation of retinal progenitors during neurogenesis and maturation of postmitotic neurons. Together, these results demonstrate the complex role of the distribution of Numb within progenitors and postmitotic neurons.

Alternative Splicing↗
PubMed2004

Senseless is required for pupal retinal development in Drosophila.

Drosophila sensory organs are specified by a family of proneural genes which induce the expression of several common targets. One such target is senseless, which encodes a zinc finger transcription factor. We analyzed the function of senseless during pupal retinal development and found that senseless is required for recruitment of both cone and pigment cells, the pupal-derived ommatidial support cells. We also found that Senseless is expressed in neural precursors shortly after the larval-pupal transition and is both necessary and sufficient for interommatidial bristle development. Furthermore, senseless is the primary target of achaete and scute during interommatidial bristle development. We also identified several differences between the development of interommatidial bristles and other macrochaete. In particular, EGFR signaling is not required for interommatidial bristle development, nor is positive feedback regulation of proneural genes by senseless. A model for interommatidial bristle specification is presented.

Animals↗
PubMed1996

Retinal development and visual sensitivity of young Pacific sockeye salmon (Oncorhynchus nerka)

The development of photoreceptor cell types and the visual sensitivity of young sockeye salmon were examined. In contrast to previous findings from rainbow trout, rod outer segments were observed in the embryo 1.5 weeks before hatching. At this stage, a full square mosaic with accessory corner cones was visible in the central retina. Post-hatching retinal development is similar to that of other fish species. During the first 11 months of development, the fibrous and interplexiform layers, the outer nuclear layer, the visual cell layer and the retinal pigment epithelium thicken. The ganglion cell layer and the inner nuclear layer regress. In addition, the mean diameter of the cones increases, with that of double cones increasing faster than that of either of the single cone types. As is the case for other salmonids, the density of accessory corner cones diminishes after smoltification (a developmental stage in salmonids). The retina of smolts exhibits a full square mosaic pattern in some peripheral areas and near the central embryonic fissure. However, unlike findings from rainbow trout, compound action potential recordings from the optic nerve of smolt sockeye reveal the presence of four cone mechanisms with sensitivity maxima at 380 (ultraviolet), 425 (short), 520 (middle) and 635 nm (long wavelength). There is also a rod mechanism with maximum sensitivity around 530 nm. Smolts also exhibit polarization sensitivity to 380 nm light under a white crepuscular background.

Journal Article↗
PubMed1992

Retinal development in very-low-birth-weight infants fed diets differing in omega-3 fatty acids.

Full-field electroretinograms (ERGs) were obtained from very-low-birth-weight (VLBW) neonates to determine whether omega-3 (omega-3) fatty acids are essential for normal human retinal development. Eighty-one infants born at 30.4 (standard deviation, +/- 1.5) wk gestation were, within 10 d of birth, either enrolled to receive mother's milk (naturally containing both omega-6 and omega-3 essential fatty acids) or randomized to receive one of the infant formulas. Corn oil-based Formula A contained mainly linoleic acid (18:2 omega-6) and was low in all omega-3 fatty acids. Soy oil-based Formula B contained ample alpha-linolenic acid (18:3 omega-3) but no long-chain omega-3. Formula C, supplemented with both alpha-linolenic acid and marine oils, was comparable to human milk in long-chain omega-3. Full-field ERGs were obtained in the special care nursery from infants aged 36 and 57 wk postconception. Ten healthy preterm infants born at 35 wk gestation were tested at 36 wk postconception. Significant differences were found among groups in rod ERG function. Post hoc comparisons showed that infants fed Formula A had significantly higher rod thresholds than infants receiving long-chain omega-3 (human milk, Formula C, and intrauterine). Infants receiving Formula B had intermediate thresholds that were significantly higher than those of infants receiving intrauterine nutrition. Analysis of the leading edge of the a-wave showed that b-wave differences originated at the photoreceptor level. Differences were not present in infants at 57 wk postconception. No significant differences among groups were found in cone b-waves at 36 or 57 wk postconception. Oscillatory potentials had significantly longer implicit times at 57 wk postconception in infants fed Formula A than in infants receiving human milk. These findings suggest that retinal function varies with the dietary supply of omega-3 fatty acids in VLBW infants.

Breast Feeding↗
PubMed1999

Early retinal development in the zebrafish, Danio rerio: light and electron microscopic analyses.

The morphological differentiation of the zebrafish retina was analyzed by using light (LM) and transmission electron (TEM) microscopy between the time of initial ganglion cell differentiation (approximately 32 hours postfertilization; hpf) and shortly after the point when the retina appears functional (approximately 74 hpf), i.e., when all major cell types and basic synaptic connections are in place. The results show that the inner retinal neurons, like the photoreceptor and ganglion cells, differentiate first within the ventronasal region, and differentiation subsequently spreads asymmetrically into the nasal and dorsal regions before reaching the ventrotemporal retina. In addition, we show that the attenuation of the optic stalk occurs in parallel with ganglion cell differentiation between 32 and 40 hpf. The first conventional synapses appear within the inner plexiform layer simultaneously with the first photoreceptor outer segment discs at 60 hpf; functional ribbon triads arise within photoreceptor synaptic terminals at 65 hpf; and synaptic ribbons occur within bipolar cell axon terminals at the time larvae exhibit their first visual responses (approximately 70 hpf). Although development is initially more advanced within the ventronasal region between 50 and 60 hpf, development across the retina rapidly equilibrates such that it is relatively comparable within all quadrants of the central retina by 70 hpf. An area within the temporal retina characterized by tightly packed and highly tiered cones emerges with subsequent development. Retinal differentiation in the zebrafish corresponds with that generally described in other vertebrates and can be correlated with the development of visual and electroretinographic responses in the animal.

Animals↗
PubMed2004

Wnt/frizzled signaling during vertebrate retinal development.

Multiple signaling pathways are known to be involved in regulating development of the vertebrate neural retina. Recent publications have demonstrated that Wnt/Frizzled (Fz) signaling components are expressed in the developing retina and may play a fundamental role in retinogenesis. In this review, we summarize Wnt/Fz expression patterns in the developing vertebrate retina, mainly from chick and mouse, and compare them with Wnt/beta-catenin reporter activity. Consistent with the dynamic expression patterns of Wnt pathway components, evidence suggests that Wnt/Fz signaling has multiple roles during retinal development.

Animals↗
PubMed2005

Expression profile of heat shock protein 108 during retinal development in the chick.

In the developing chick retina, heat shock protein 108 (HSP108), which exhibits transferrin binding activity, has been demonstrated at the mRNA level, while transferrin shows two expression peaks. Here, we investigated the expression profile of HSP108 in the developing chick retina at the protein level. The localization of HSP108 in embryonic days 15 (E15), E18, and postnatal day 2 (P2) chick retina was examined immunohistochemically using monoclonal antibody 9G10 specific for chick HSP108, while the expression levels of HSP108 in developing chick retina from E12 to P2 and adult were measured by Western blot analysis. HSP108 was expressed in the ganglion cell layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, inner segments of photoreceptors and retinal pigment epithelium. Two peaks of HSP108 expression were found at around E13 and E18, respectively. Since the two HSP108 peaks appeared to be correlated with the transferrin expression peaks during retinal development, HSP108 may be associated with iron metabolism during the development of the retina.

Animals↗
PubMed2002

A Role for phosphoinositide 3-kinase in the control of cell division and survival during retinal development.

Neurogenesis in the retina requires the concerted action of three different cellular processes: proliferation, differentiation, and apoptosis. Class IA phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85 regulatory and a p110 catalytic subunit. p110alpha has been shown to regulate cell division and survival. Little is known of its function in development, however, as p110alpha knockout mice exhibit CNS defects, but death at early embryonic stages impairs further study. Here, we examine the role of PI3K in mouse retina development by expressing an activating form of PI3K regulatory subunit, p65(PI3K), as a transgene in the retina. Mice expressing p65(PI3K) showed severely disrupted retina morphogenesis, with ectopic cell masses in the neuroepithelium that evolved into infoldings of adult retinal cell layers. These changes correlated with an altered cell proliferation/cell death balance at early developmental stages. Nonetheless, the most affected cell layer in adult retina was that of photoreceptors, which correlated with selectively increased survival of these cells at developmental stages at which cell division has ceased. These results demonstrate the relevance of accurate PI3K regulation for normal retinal development, supporting class IA PI3K involvement in induction of cell division at early stages of neurogenesis. These data also show that, even after cell division decline, PI3K activation mediates survival of differentiated neurons in vivo.

Animals↗
PubMed1997

The albino retina: an abnormality that provides insight into normal retinal development.

Albino mammals have specific deficits in their retinae and in the pattern of decussation at their optic chiasm, demonstrating that a melanin-related agent is crucial for normal development of the visual system. Although much attention has been paid to chiasmatic abnormality over the past 30 years, little progress has been made in understanding the abnormality. There has now been a shift of attention towards an analysis of the developing albino retina, which is providing significant advances in our understanding of the role played by this melanin-related agent. It is now possible to identify one candidate substance that emanates from the synthetic pathway of melanin that plays a key role in regulating retinal development.

Animals↗
PubMed2005

Distinct developmental programs require different levels of Bmp signaling during mouse retinal development.

The Bmp family of secreted signaling molecules is implicated in multiple aspects of embryonic development. However, the cell-type-specific requirements for this signaling pathway are often obscure in the context of complex embryonic tissue interactions. To define the cell-autonomous requirements for Bmp signaling, we have used a Cre-loxP strategy to delete Bmp receptor function specifically within the developing mouse retina. Disruption of a Bmp type I receptor gene, Bmpr1a, leads to no detectable eye abnormality. Further reduction of Bmp receptor activity by removing one functional copy of another Bmp type I receptor gene, Bmpr1b, in the retina-specific Bmpr1a mutant background, results in abnormal retinal dorsoventral patterning. Double mutants completely lacking both of these genes exhibit severe eye defects characterized by reduced growth of embryonic retina and failure of retinal neurogenesis. These studies provide direct genetic evidence that Bmpr1a and Bmpr1b play redundant roles during retinal development, and that different threshold levels of Bmp signaling regulate distinct developmental programs such as patterning, growth and differentiation of the retina.

Animals↗
PubMed2001

Glutamate-mediated responses in developing retinal ganglion cells.

Glutamate has been suggested to regulate the development of retinal ganglion cells, but little is known about the functional properties of glutamate receptors during ontogeny of these neurons. Using whole-cell and outside-out patch-clamp recordings, we have characterized the pharmacological, rectification, and kinetic properties of ionotropic glutamate receptors in ganglion cells isolated from fetal and postnatal cat retinas. The fetal cells were studied at embryonic day 33 (E33) to E38, before significant outgrowth of their dendritic processes and prior to the formation of synaptic contacts in the inner plexiform layer. In several respects, the functional properties of early fetal ganglion cells were found to be remarkably similar to those of postnatal cells. In both age groups, glutamate and AMPA produced fast desensitizing currents, kainate yielded large steady-state currents, while applications of NMDA resulted in multiple channel openings. The shapes and amplitudes of these glutamate-gated currents were also similar and the current-voltage relations were nearly linear, with reversal potentials near 0 mV. Moreover, the dose-response curves (to kainate) were virtually identical in the fetal and postnatal neurons. The proportion of neurons responsive to NMDA and non-NMDA agonists was nearly the same in both age groups. This early functional expression of glutamate receptors cannot be involved in the transmission of electrical information in the developing retina because at this stage few ganglion cells are capable of generating action potentials (Skaliora et al., 1993). It is suggested that the early activation of NMDA and non-NMDA receptors in fetal ganglion cells may regulate the outgrowth and stabilization of dendritic processes in these neurons. Our data also revealed some differences in the responses of fetal and postnatal cells to glutamate and its agonists. Thus, the unitary NMDA conductance was found to decrease with age, while the rate of glutamate receptor desensitization increased with age. Also, while virtually all postnatal cells responded to glutamate, the proportion of fetal cells that manifested glutamate-mediated responses was lower. These maturational changes presumably allow retinal ganglion cells to integrate synaptic inputs for the transmission of electrical signals to the visual centers of the brain.

Animals↗
PubMed1995

Natural course of retinal development in preterm infants without threshold retinopathy.

In a consecutive series, 209 preterm infants with birth weights below 1501 g or a gestational age of < or = 32 weeks were observed. Stage 3 retinopathy of prematurity (ROP) developed in 48 infants (23%) of between 32 and 46 weeks postconceptional age (PCA; mean, 37 weeks). Stage 3 ROP was not seen before 6 weeks after birth. Threshold ROP was seen and treated at between 34 and 42 weeks PCA (mean, 38 weeks PCA; n = 22, 10.5%). A subgroup of 126 untreated infants were followed until complete retinal vascularisation. At estimated term, 38.7% of eyes with vessels ending in zone 3 at the first examination showed complete vascularisation as compared with 17.6% of eyes with vessels ending in peripheral zone 2 and none of those with vessels ending in central zone 2. Occurrence of ROP delayed retinal development. At estimated term, no eye with any stage of ROP showed complete vascularisation as compared with 35.4% of eyes without ROP. Regression of stage 3 ROP below threshold started in all cases before 56 weeks PCA.

Cryosurgery↗
PubMed1990

Immunolabelling by a newt retinal pigment epithelium antibody during retinal development and regeneration.

The binding of RPE-1, a mouse monoclonal antibody selective for newt retinal pigment epithelium, was followed in eyes undergoing embryonic development and retinal regeneration. Using the indirect immunofluorescence technique on frozen sections, we observed bright and continuous labelling exclusively in the retinal pigment epithelium (RPE) of normal adult newts, but labelling became diminished near the ora serrata region and stopped abruptly at the ciliary margin. During development, labelling was not detected in the retinal pigment epithelium (RPE) until the formation of photoreceptor outer segments and was not observed in any other ocular tissue. There was no correlation between the appearance of pigment in retinal pigment epithelial cells and their labelling with the RPE-1 antibody. Furthermore, albino salamander embryos showed the same pattern of labelling with RPE-1 as that seen in age-matched pigmented animals. During retinal regeneration, RPE cells were labelled less intensely, but heavy labelling was observed in the newly formed retinal cells. With time, labelling in regenerated retina receded, so that by the end of regeneration, labelling by RPE-1 was once more restricted to the RPE cells. The identification of RPE-1 as a marker for postmitotic retinal neurons about to undergo differentiation provides a promising approach for further studies of regeneration with the help of molecular tools.

Albinism↗