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PubMed2003

Targeted expression of the dominant-negative FGFR4a in the eye using Xrx1A regulatory sequences interferes with normal retinal development.

Molecular analysis of vertebrate eye development has been hampered by the availability of sequences that can selectively direct gene expression in the developing eye. We report the characterization of the regulatory sequences of the Xenopus laevis Rx1A gene that can direct gene expression in the retinal progenitor cells. We have used these sequences to investigate the role of Fibroblast Growth Factor (FGF) signaling in the development of retinal cell types. FGFs are signaling molecules that are crucial for correct patterning of the embryo and that play important roles in the development of several embryonic tissues. FGFs and their receptors are expressed in the developing retina, and FGF receptor-mediated signaling has been implicated to have a role in the specification and survival of retinal cell types. We investigated the role of FGF signaling mediated by FGF receptor 4a in the development of retinal cell types in Xenopus laevis. For this purpose, we have made transgenic Xenopus tadpoles in which the dominant-negative FGFR4a (Delta FGFR4a) coding region was linked to the newly characterized regulatory sequences of the Xrx1A gene. We found that the expression of Delta FGFR4a in retinal progenitor cells results in abnormal retinal development. The retinas of transgenic animals expressing Delta FGFR4a show disorganized cell layering and specifically lack photoreceptor cells. These experiments show that FGFR4a-mediated FGF signaling is necessary for the correct specification of retinal cell types. Furthermore, they demonstrate that constructs using Xrx1A regulatory sequences are excellent tools with which to study the developmental processes involved in retinal formation.

Animals↗
PubMed1998

Putative functions of fibroblast growth factors in retinal development, maturation and survival.

The understanding of growth factor functions in the central nervous system is of paramount importance. They participate in all stages of neural development, maintenance and survival and are implicated in many pathological states. The complexity of the regulation of these signalling molecules and the intricate structure of brain tissue has made progress towards these goals difficult. The vertebrate retina has long been utilised as a model for development and function of the CNS owing to it's accessibility, organisation and composition. This is also true for growth factor research. This review will attempt to discuss some recent data, particularly with respect to the fibroblast growth factor family and highlight where more work is required for two areas of research: (1) the physiological role(s) of growth factors in retinal development and function; and (2) the potential use of growth factors in neuroprotection.retina, photoreceptor, development, survival, growth factors in neuroprotection.

Animals↗
PubMed1995

Basic fibroblast growth factor in retinal development: differential levels of bFGF expression and content in normal and retinal degeneration (rd) mutant mice.

The spatial and temporal patterns of expression and content of bFGF during postnatal development of the retina were established in C57BL/6J mice. Western blot analysis, using an anti-rodent bFGF antibody, shows multiple molecular weights of 18, 20.5, and 22 kDa of bFGF protein isolated from the adult retina. A bioassay indicates that this putative basic fibroblast growth factor (bFGF) stimulates proliferation of BALB/c 3T3 fibroblasts in a dose-dependent manner identical to an authentic bFGF standard. Immunocytochemistry reveals that bFGF immunoreactivity is located primarily in the immature photoreceptors during postnatal development and is associated with the photoreceptor outer segment/interphotoreceptor matrix complex in the adult retina. bFGF mRNA expression pattern and levels were evaluated using mouse bFGF riboprobes with in situ hybridization and quantitative ribonuclease protection assay. bFGF mRNA expression is not detectable in the retina until Postnatal Day 10 (P10), although high levels of bFGF mRNA signals were consistently observed in astrocytes in the optic disc at all postnatal ages examined. From P10 to the adult stage, bFGF mRNA was localized mainly to the photoreceptor inner segments, and the bFGF mRNA levels were approximately the same at P10 and in the adult retina. The patterns of retinal bFGF expression and content during normal development established above were compared to these parameters in the retina of rd (C57BL/6J rd/rd), a spontaneous mouse mutant in which photoreceptors degenerate shortly after birth. More bFGF immunoreactivity was detected in the outer retina during photoreceptor degeneration than was present in normal photoreceptors at equivalent ages. Densitometry measurements indicate that the level of immunoreactivity is 56% to 1.8-fold higher in rd than in the normal retina between P6 and P10, respectively. This is at least partially due to elevated bFGF mRNA expression in rd retinas during photoreceptor degeneration. In situ hybridization showed more intense bFGF mRNA hybridization signals in rd photoreceptors from P10 to P15, and RNase protection assay demonstrated much higher hybridization signals in rd retinas from P6 to P10 than in the normal retinas at these stages. More bFGF mRNA hybridization signals were also present in some cells in the inner nuclear layer following photoreceptor cell death in the rd retina but were only weakly evident in the inner nuclear layer in the normal adult retina. These results provide the first evidence that a naturally occurring neuronal degeneration is accompanied by elevated expression of bFGF in degenerating neurons prior to cell death.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1991

Cell-surface regulation of beta 1-integrin activity on developing retinal neurons.

Integrins are a family of alpha beta heterodimeric receptors that mediate cell-cell and cell-substratum interactions. Integrin binding to extracellular ligands regulates cell adhesion, shape, motility, intracellular signalling and gene expression. Mechanisms that regulate integrin function are, therefore, central to the participation of integrins in a diverse set of cellular events. Here we report the identification of TASC, a monoclonal antibody to a novel epitope on the integrin beta 1 subunit, which inhibits cell adhesion to vitronectin but promotes adhesion to laminin and collagen types I and IV. We show that developing retinal neurons that have lost responsiveness to laminin regain the ability to bind laminin in the presence of TASC. Thus, beta 1-class integrins are likely to occupy multiple affinity states that can be modulated at the cell surface.

Amino Acid Sequence↗
PubMed2006

Rab11-FIP4 is predominantly expressed in neural tissues and involved in proliferation as well as in differentiation during zebrafish retinal development.

Rab11 family interacting protein 4 (Rab11-FIP4) was initially identified in humans as an Rab11-binding protein, but its biological function has remained unknown. We cloned the zebrafish orthologue of Rab11-FIP4 (zRab11-FIP4) and analyzed its function in vivo by using antisense morpholino. zRab11-FIP4 was expressed as 2 alternative transcripts, i.e., the longer A-form predominantly expressed in neural tissues and the shorter B-form expressed ubiquitously; and in situ hybridization revealed that the A-form was the dominant form. In the developing retina, zRab11-FIP4 was expressed in progenitors throughout the retina at early stages; and then, along with the differentiation, the expression became gradually restricted to the ganglion cell layer and ciliary marginal zone. zRab11-FIP4A knockdown embryos exhibited eye phenotypes similar to those of the shh mutant, such as a small eye with impaired cell proliferation and the delay in cell-cycle exit and differentiation of retinal progenitors. The lack of induction of p57kip2 and enhanced expression of cyclin D1 were observed in the morphant retina. Importantly, the delay in cell-cycle exit was rescued by ectopic expression of either p57Kip2 or dominant-negative PKA, suggesting that Rab11-FIP4A plays pivotal roles in retinal development by regulating Shh signaling and a mechanism acting in parallel with Shh signaling in the control of cell-cycle exit.

Animals↗
PubMed2002

Changing patterns of ganglion cell coupling and connexin expression during chick retinal development.

We have used dye injection and immunolabeling to investigate the relationship between connexin (Cx) expression and dye coupling between ganglion cells (GCs) and other cells of the embryonic chick retina between embryonic days 5 and 14 (E5-14). At E5, GCs were usually coupled, via soma-somatic or dendro-somatic contacts, to only one or two other cells. Coupling increased with time until E11 when GCs were often coupled to more than a dozen other cells with somata in the ganglion cell layer (GCL) or inner nuclear layer (INL). These coupled clusters occupied large areas of the retina and coupling was via dendro-dendritic contacts. By E14, after the onset of synaptogenesis and at a time of marked cell death, dye coupling was markedly decreased with GCs coupled to three or four partners. At this time, coupling was usually to cells of the same morphology, whereas earlier coupling was heterogeneous. Between E5 and E11, GCs were sometimes coupled to cells of neuroepithelial morphology that spanned the thickness of the retina. The expression of Cx 26, 32, and 43 differed and their distribution changed during the period studied, showing correlation with events such as proliferation, migration, and synaptogenesis. These results suggest specific roles for gap junctions and Cx's during retinal development.

Animals↗
PubMed1992

Expression of carnosine-like immunoreactivity during retinal development in the clawed frog (Xenopus laevis).

The development of neurons immunoreactive to carnosine (beta-alanyl-L-histidine) was studied in the retina of Xenopus laevis during the premetamorphic period. Carnosine-like immunoreactivity was detected in photoreceptors from stage 39/40 (according to Nieuwkoop and Faber [Normal Tables of Xenopus laevis (Daudin), Elsevier, Amsterdam, 1956]) and in bipolar cells and their processes in the inner plexiform layer from stage 44/45. At all the developmental stages studied, neuroepithelial cells at the ciliary margin were completely unstained, suggesting that carnosine is only present in postmitotic retinal neurons. This study demonstrates a correlation between the times of appearance of carnosine-like immunoreactivity during retinal development and the onset of visual function.

Animals↗
PubMedDate not supplied

Rod photopigment deficits in albinos are specific to mammals and arise during retinal development.

Adult albino mammals have specific retinal defects, including reduced numbers of rod photoreceptors. To examine when this rod deficit arises and whether it exists in nonmammalian albinos, we have used absorbance spectrophotometry to measure photopigment levels in dark-adapted eyes taken from three groups of pigmented and albino animals: adult rodents (rats and mice), developing rats, and mature Xenopus frogs. Rhodopsin concentrations were consistently and significantly reduced in mammalian albinos compared to their wild-type counterparts from before the time of eye opening, but photopigment levels were similar in frogs of both pigmentation phenotypes. The results strongly suggest that deficits in the rod cell population arise early in development of the mammalian albino retina, but do not generalize to nonmammalian mutants lacking retinal melanin.

Albinism, Ocular↗
PubMed1997

Evidence that tyrosine phosphorylation regulates N-cadherin turnover during retinal development.

N-cadherin, a member of the cadherin family of calcium-dependent cell adhesion molecules, mediates adhesive and signaling interactions between cells during development. N-Cadherin undergoes dynamic spatiotemporal changes in expression which correlate with morphogenetic movements of cells during organogenesis and histogenesis. We have previously shown that N-cadherin expression during development is regulated by several mechanisms, including mRNA expression, cytokine modulation, and proteolytically mediated turnover, yielding the NCAD90 protein. The present study was directed at determining the extent to which N-cadherin in primary embryonic cells is the target of endogenous kinases and phosphatases, as well as the effects of modulation of these enzymes on NCAD90 expression. The results of phosphoamino acid analyses, peptide mapping, and measurements of N-cadherin and NCAD90 expression in embryonic tissues indicate that N-cadherin is indeed the target of endogenous kinase and phosphatase action, and that modulation of different classes of these enzymes can result in either stimulation or inhibition of NCAD90 production. These results provide a mechanistic explanation for observations that cadherin function is downregulated following expression of exogenously introduced viral tyrosine kinases and provide a function for the tyrosine phosphatases recently found in association with cadherins. The results indicate that N-cadherin expression during retinal development is possibly regulated in part by modulation of its phosphorylation state, the balance of which may determine whether N-cadherin remains stably expressed or is targeted for proteolytically mediated turnover to produce NCAD90.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2004

Alcohol-induced lipid and morphological changes in chick retinal development.

BACKGROUND: Alcohol exposure causes alterations in the lipid content of different organs and a reduction of long-chain fatty acids. During embryo development, the central nervous system is extremely vulnerable to the teratogenic effects of alcohol, and the visual system is particularly sensitive. METHODS: White Leghorn chick embryos were injected with 10- and 20-microl alcohol doses into the yolk sac at day 6 of incubation. The lipid composition of the retina was analyzed in embryos at day 7 of incubation (E7), E11, E15, and E18. The percentages of phospholipids, free cholesterol, esterified cholesterol, diacylglycerides, and free fatty acids were estimated by using an Iatroscan thin layer chromatography flame ionization detector. Gas chromatography and mass spectrometry were used to determine fatty acid composition. The morphological study was performed at E7, E11, and E19 by means of semithin and immunohistochemical techniques. RESULTS: In the retina, alcohol causes the total lipid content to change, with a remarkable increase in free cholesterol and a dramatic decrease in esterified cholesterol. Diacylglycerides and free fatty acids tend to increase. Phosphatidylcholine and phosphatidylethanolamine decrease, whereas phosphatidylserine, sphingomyelin, and phosphatidylinositol increase. The main fatty acids of the retina also undergo changes. At E7, myriotic acid increases, and oleic acid and polyunsaturated fatty acids such as arachidonic acid and docosahexaenoic acid decrease. From E18 onward, there is some recovery, except for fatty acids, which recover earlier. From a morphological point of view, alcohol effects on retinal development are various: increase of intercellular spaces in all cell layers, pyknosis with loss of cellularity in the inner nuclear cell layer and ganglion cell layer, retarded or disorderly cell migration, early cell differentiation, and loss of immunoreactivity for myelin oligodendrocyte-specific protein. CONCLUSIONS: Acute alcohol exposure during embryo development causes the lipid composition of the retina to change, with a trend to recovery in the last stages. These alterations are in line with the changes observed at a morphological level.

Animals↗
PubMed2001

Effects of docosahexaenoic acid on retinal development: cellular and molecular aspects.

We have recently shown that docosahexaenoic acid (DHA) is necessary for survival and differentiation of rat retinal photoreceptors during development in vitro. In cultures lacking DHA, retinal neurons developed normally for 4 d; then photoreceptors selectively started an apoptotic pathway leading to extensive degeneration of these cells by day 11. DHA protected photoreceptors by delaying the onset of apoptosis; in addition, it advanced photoreceptor differentiation, promoting opsin expression and inducing apical differentiation in these neurons. DHA was the only fatty acid having these effects. Mitochondrial damage accompanied photoreceptor apoptosis and was markedly reduced upon DHA supplementation. This suggests that a possible mechanism of DHA-mediated photoreceptor protection might be the preservation of mitochondrial activity; a critical amount of DHA in mitochondrial phospholipids might be required for proper functioning of these organelles, which in turn might be essential to avoid cell death. Müller cells in culture appeared to be involved in DHA processing: they took up DHA, incorporated it into glial phospholipids, and channeled it to photoreceptors in coculture. Both Müller cells, when cocultured with neuronal cells, and the glial-derived neurotrophic factor (GDNF) protected photoreceptors from cell death. These results suggest that glial cells may play a central role in regulating photoreceptor survival during development through the provision of trophic factors. The multiple effects of DHA on photoreceptors suggest that, in addition to its structural role, DHA might be one of the trophic factors required by these cells.

Animals↗
PubMed1990

Angiogenesis in normal human retinal development: the involvement of astrocytes and macrophages.

Recent studies have suggested a role for mononuclear phagocytes series (MPS) cells in neovascularisation associated with retinal pathology and experimentally induced subretinal neovascularisation. The present study is concerned with the normal development of the human retinal vasculature. Morphological details are provided of developing vascular structures including the formation of tight junctions and canalisation of angioblast cords. The relationships of astrocytes and pericytes to developing structures and the presence of a perivascular collagenous matrix are described. Ultrastructural and histochemical analyses reveal an association between MPS cells and developing vascular structures. It is suggested that MPS cells may influence angiogenesis in normal retinal development, as well as in retinal pathology.

Astrocytes↗
PubMed1998

The genetic sequence of retinal development in the ciliary margin of the Xenopus eye.

The ciliary marginal zone is a perpetually self-renewing proliferative neuroepithelium at the perimeter of the retina in amphibians and fish. In the ciliary marginal zone (CMZ), cells are spatially ordered with respect to cellular development, deep stem cells being most peripheral and differentiating retinal progenitors being most central. This spatial gradient in the CMZ recapitulates embryonic retinogenesis and provides a powerful system to examine the relative order of gene expression during this process. A number of neurogenic and proneural genes have been described to have interacting roles in the development of the vertebrate nervous system, and so it is of major importance to put these genes in a hierarchical pathway. In no other system yet described are the developmental stages of neurogenesis arrayed so clearly in a spatial pattern as in the CMZ. We have therefore taken advantage of this system, using double in situ hybridizations on cross sections of the CMZ, to compare the spatial patterns of 15 proneural, neurogenic, and other genes involved in early and late phases of retinal development. In addition, we have positioned these expression patterns with respect to cell division. What emerges from this work is a spatial ordering of gene expression that predicts a genetic hierarchy governing vertebrate retinogenesis. By injecting messenger RNA for some of these genes into blastomeres of the Xenopus embryo and examining the effects on expression of the putative downstream genes, we have been able to corroborate some of the relationships between genes predicted to act sequentially.

Animals↗
PubMed1992

Retinal fate and ganglion cell differentiation are potentiated by acidic FGF in an in vitro assay of early retinal development.

One of the earliest events in vertebrate eye development is the establishment of the pigmented epithelium and neural retina. These fundamentally different tissues derive from the invaginated optic vesicle, or optic cup. Even after achieving a fairly advanced state of differentiation, the pigmented epithelium exhibits the same potential as the optic cup in that it can "transdifferentiate" into neural retina. C. M. Park and M. J. Hollenberg (Dev. Biol. 134, 201-205, 1989) discovered that administration of basic fibroblast growth factor, coupled with retinal removal, could trigger this transformation in vivo. We have developed a quantitative in vitro assay to study the role(s) of the fibroblast growth factor (FGF) family in this phenomenon and more generally in early retinal development. We found that several aspects of the process, including inhibition of pigmented epithelium differentiation, proliferation, and conversion to a retinal fate, were not strictly correlated. Both acidic and basic FGFs were found to potentiate all aspects of the process, with acidic FGF being 4 to 20 times more potent than basic FGF for inhibition of pigmentation and induction of retinal antigens. Depending upon its concentration, acidic FGF induced from 40% to 80% of the cells in the explants to produce antigens normally expressed by retinal ganglion cells, the first cell type to be generated in retinal development. Expression of such a ganglion cell marker could be directly stimulated in non-dividing cells as well as in dividing cells, indicating that conversion from the pigmented epithelial to retinal fate did not require cell division. These data suggest that acidic FGF, or a related molecule, may function in establishment of retinal fate from the optic cup. This effect may be directly or indirectly mediated by induction of retinal ganglion cell fate among multipotent progenitor cells.

Animals↗
PubMed2001

Expression of the 67 kDa laminin receptor (67LR) during retinal development: correlations with angiogenesis.

Interaction of vascular cells with the laminin component of basement membranes is important for normal cell function. Likewise, abnormal interactions may have a critical role in vascular pathology. It has been previously demonstrated that the 67 kDa laminin receptor (67LR) is expressed at high levels during proliferative retinopathy in a mouse model and in the current study we have examined 67LR in the neonatal mouse to determine if this receptor plays a role in aspects of developmental angiogenesis in the developing murine retina. Groups of C57/BL6 mice were killed at postnatal day P1, P3, P5, P7, P9 and P11 to assess the retinal vasculature. A number of mice were perfused with FITC-dextran and the eyes removed, fixed in 4% paraformaldehyde (PFA) and flat-mounted for confocal scanning laser microscopy. The eyes from the remaining mice were either placed in 4% PFA and embedded in paraffin-wax, or had the neural retina dissected off and total RNA or protein extracted. Immunofluorescence, in situ hybridization, quantitative reverse transcriptase polymerase chain reaction and Western blotting analysis were employed to locate and determine expression levels of 67LR. Both 67LR mRNA and protein expression showed a characteristic bi-phasic expression pattern which correlated with key stages of retinal vascular development in the murine retina. 67LR showed high expression levels at P1 (P < 0.05) (correlating with superficial vascular plexus formation) and at P7 (P < 0.05) (correlating with deep vascular plexus formation). Conversely, 67LR expression was decreased when active angiogenic activity was lowest. Significantly, optical sectioning of retinal flat-mounts revealed high levels of 67LR expression in developing segments of both superficial and deep capillary plexi, a pattern which co-localized strongly with laminin. 67LR is regulated during post-natal development of the retinal vasculature. High levels of 67LR during the two well-defined phases of retinal capillary plexus formation suggests that this receptor may play an important role in retinal angiogenesis.

Animals↗
PubMed1985

Retinal development in humans: the roles of differential growth rates, cell migration and naturally occurring cell death.

The distribution of ganglion cells throughout the retinal ganglion cell layer is non-uniform in adult mammals. This paper reviews some of our data describing the development of retinal ganglion cell topography in the human fetus. Results indicated that early in the fetal period the distribution of cells in the ganglion cell layer is almost uniform, but by the end of gestation there is a gradient in cell density of about 10:1 (central:peripheral). Peripheral retina grows more rapidly than the central retina prior to about 23 weeks gestation, but this differential growth rate apparently has little effect on the development of a centro-peripheral density gradient. The gradient appears between about 18 and 30 weeks gestation, and during this period there appears to be a greater rate of cell death in the ganglion cell layer of the peripheral retina. Cell density at the developing fovea is less than the perifoveal cell density at all ages, suggesting that ganglion cells migrate from foveal into perifoveal regions throughout the fetal period.

Cell Count↗
PubMedDate not supplied

Retinal development of West Australian dhufish, Glaucosoma hebraicum.

An investigation of retinal specializations was carried out in larval and juvenile dhufish, Glaucosoma hebraicum (Glaucosomidae, Teleostei). The development of photoreceptors and formation of the retinal mosaic was followed by light and electron microscopy. At hatching the eye was undifferentiated. Cone photoreceptors were present by day 3 posthatch (dph), when exogenous feeding began. Single and multiple cones were present in a row arrangement from 3 dph to 20 dph, when the first rod nuclei were observed. Between 20 dph and approximately 3 months posthatch (mph), the row arrangement was replaced by a square mosaic of four double cones surrounding a single cone, and the cones increased in size, with the outer segments reaching up to 30 microm in length. During the period of spatial rearrangement, triple cones were often observed. From their first appearance, rod photoreceptors were added rapidly. Investigation of ganglion cell topography in 3-mph fish that had attained the adult-like square photoreceptor mosaic was carried out using retinal wholemounts. The highest densities of neurones in the ganglion cell layer were in temporal retina but no well-defined area centralis was observed. Microspectrophotometric measurements of the visual pigments within the outer segments of the photoreceptors of 3-mph fish revealed double cones with identical absorption spectra in each member of the outer segment, and the wavelength of maximum absorption (lambda(max)) located at 522 nm. Single cones were found to possess a visual pigment with lambda(max) at 460 nm and rods with a lambda(max) of 498 nm. The results imply that the larvae and juveniles are adapted for survival in coastal waters and may be active in relatively low light levels from early stages of development.

Animals↗
PubMed2004

BDNF regulates NMDA receptor activity in developing retinal ganglion cells.

Brain-derived neurotrophic factor (BDNF) modulates glutamate receptors of the NMDA type in many areas of the brain. We assessed whether BDNF exerts an effect on NMDA receptor properties in retinal ganglion cells during early postnatal development. Electrophysiological responses to the glutamate agonist NMDA (500 microM-2 mM) in retinal slices of wildtype and BDNF deficient mice (bdnf-/-) were recorded using the whole-cell patch-clamp technique. Retinal ganglion cells of bdnf-/- mice displayed significantly smaller NMDA currents than those of age-matched wildtype mice. Remarkably, NMDA receptor activity was restored by incubating retinal slices of bdnf-/- mice in BDNF (50 ng/ml) for 1-3 h. We suggest that BDNF plays a role in the activation of functional NMDA receptors in early ganglion cell development.

Animals↗