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M M LaVail

Publications and source records attributed to M M LaVail.

At least 19 recordsLinked to original sources
PubMed1992

Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light.

Recent demonstrations of survival-promoting activity by neurotrophic agents in diverse neuronal systems have raised the possibility of pharmacological therapy for inherited and degenerative disorders of the central nervous system. We have shown previously that, in the retina, basic fibroblast growth factor delays photoreceptor degeneration in Royal College of Surgeons rats with inherited retinal dystrophy and that the growth factor reduces or prevents the rapid photoreceptor degeneration produced by constant light in the rat. This light-damage model now provides an efficient way to assess quantitatively the survival-promoting activity in vivo of a number of growth factors and other molecules. We report here that photoreceptors can be significantly protected from the damaging effects of light by intravitreal injection of eight different growth factors, cytokines, and neurotrophins that typically act through several distinct receptor families. In addition to basic fibroblast growth factor, those factors providing a high degree of photoreceptor rescue include brain-derived neurotrophic factor, ciliary neurotrophic factor, interleukin 1 beta, and acidic fibroblast growth factor; those with less activity include neurotrophin 3, insulin-like growth factor II, and tumor necrosis factor alpha; those showing little or no protective effect are nerve growth factor, epidermal growth factor, platelet-derived growth factor, insulin, insulin-like growth factor I, heparin, and laminin. Although we used at least one relatively high concentration of each agent (the highest available), it is still possible that other concentrations or factor combinations might be more protective. Injecting heparin along with acidic fibroblast growth factor or basic fibroblast growth factor further enhanced the degree of photoreceptor survival and also suppressed the increased incidence of macrophages produced by either factor, especially basic fibroblast growth factor. These results now provide the impetus for determining the normal function in the retina, mechanism(s) of rescue, and therapeutic potential in human eye diseases for each agent.

Animals↗
PubMed1992

Genesis of neurons in the retinal ganglion cell layer of the monkey.

We have analyzed the genesis of various neuronal classes and subclasses in the ganglion cell layer of the primate retina. Neurons were classified according to their size and the time of their origin was determined by pulse labeling with 3H-thymidine administered to female monkeys 38 to 70 days pregnant. All offspring were sacrificed postnatally, and their retinas processed for autoradiography. The somata of cells in the retinal ganglion cell layer generated on embryonic day (E) 38 ranged from 9 to 14 microns in diameter. Between E40 and E56, the minimum soma diameter remained around 8-9 microns, while the maximum gradually increased to 22 microns. As a consequence, the means of the distributions of labeled cells also increased with age, from 11.8 microns diameter for cells generated on E38 to 14.6 microns diameter at E56. Over this period the percentage of labeled cells in the 10.5-16.5 microns and greater than 16.5 microns diameter range gradually increased. The proportion of the labeled cells in the less than 10.5 microns diameter range decreased from E38 to E45, but subsequently increased rapidly. At the end of neurogenesis in the retinal ganglion cell layer, around E70, most labeled cells were considerably smaller (7-9 microns) than those generated earlier. Our results indicate that within the ganglion cell layer of the macaque, neurons of small caliber are generated first, followed successively by medium sized cells. Large, putative P alpha cells are generated late. The production between E56 and E70 of cells with the smallest somata suggests that the last-generated neurons in the ganglion cell layer are predominantly displaced amacrine cells. Within the same sector of retina, different classes of neurons in the ganglion cell layer of the rhesus monkey appear to have a sequential schedule of production.

Animals↗
PubMed1992

Epi-polarization and incident light microscopy readily resolve an autoradiographic or heavy metal label from an obscuring background or second label.

Difficulty encountered in resolving grains of exposed photographic emulsion in autoradiographs of the densely melanized retinal pigment epithelium was solved by using epi-polarized or incident light microscopy. The apparatus used included a metallurgical illuminator specifically designed for epi-polarization microscopy or, as a less expensive but only slightly less effective alternative, a modified fluorescence illuminator. The black melanin granules absorb incident light (as they do in vivo) while the silver grains reflect it producing a "darkfield-like" representation. Brightfield and darkfield-like images can be alternated easily and quickly, or both can be viewed simultaneously. Epi-polarization microscopy has wider application in resolving a reflective label over any opaque background staining or dark second label.

Animals↗
PubMed1992

Immunohistochemical localization of basic fibroblast growth factor in mature and developing retinas of normal and RCS rats.

Basic fibroblast growth factor (bFGF) delays photoreceptor degeneration when injected intraocularly in Royal College of Surgeons (RCS) rats with inherited retinal dystrophy. In the present study, we have determined the localization of endogenous bFGF in retinas of normal and RCS rats during the normal developmental period (postnatal days 0-20) and the period of photoreceptor degeneration in RCS rats (days 20-90). bFGF was localized immunohistochemically by indirect immunoperoxidase using two different polyclonal antibodies and one monoclonal antibody against bFGF. bFGF was present in retinas as early as birth, and remained through adult age. Controls using either PBS, non-immune IgG or antibody preabsorbed with bFGF peptide were devoid of label. In normal rats between the ages of birth and postnatal day (P) 4, bFGF was found in developing ganglion cells, superficial blood vessels, some of the innermost cells in the neuroblastic layer, developing horizontal cells, and retinal pigment epithelial (RPE) cells. Between P0 and P4, the intensity of staining increased significantly in horizontal cells. From P6-P10, some cells in the inner nuclear layer remained positive, but horizontal cell staining became less intense in the central retina. The superficial vessels, ganglion cells and RPE cells also remained positive for bFGF. At P20-25, when the retina was essentially mature, bFGF was found in RPE cells, most cells of the ganglion cell layer, and many cells of the inner nuclear layer, but horizontal cells and blood vessels showed a lower concentration of bFGF than they did at younger ages. At P45 and older, blood vessels no longer showed bFGF immunoreactivity. The staining pattern in RCS rats was indistinguishable from that for normal rats at all ages examined. These results show that bFGF is present in the developing and adult rat retina in some neural cells, in addition to vessels and RPE cells. The transient elevated expression of bFGF immunoreactivity in developing horizontal cells and blood vessels suggests a possible role for this growth factor in retinal development. In addition, if RCS retinas possess any difference in bFGF localization or concentration compared to normal retinas, it must be too small to detect by immunohistochemical means, or at least with the reagents used.

Animals↗
PubMed1992

Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat.

Injection of basic fibroblast growth factor (bFGF) into the eye, intravitreally or subretinally, delays photoreceptor degeneration in inherited retinal dystrophy in the rat, as does local injury to the retina (Faktorovich et al., 1990). To determine whether this heparin-binding peptide or local injury is effective in any other form of photoreceptor degeneration, we examined their protective roles in light damage. Albino rats of the F344 strain were exposed to 1 or 2 weeks of constant fluorescent light (115-200 footcandles), either with or without 1 microliter of bFGF solution (1150 ng/microliters in PBS) injected intravitreally or subretinally 2 d before the start of light exposure. Uninjected and intravitreally PBS-injected controls showed the loss of a majority of photoreceptor nuclei and the loss of most inner and outer segments after 1 week of light exposure, while intravitreal injection of bFGF resulted in significant photoreceptor rescue. The outer nuclear layer in bFGF-injected eyes was two to three times thicker than in controls, and the inner and outer segments showed a much greater degree of integrity. Following recovery in cyclic light for 10 d after 1 week of constant light exposure, bFGF-injected eyes showed much greater regeneration of photoreceptor inner and outer segments than did the controls. bFGF also increased the incidence of presumptive macrophages, located predominantly in the inner retina, but the evidence suggests they are not directly involved in photoreceptor rescue. Subretinal injection of bFGF resulted in photoreceptor rescue throughout most of the superior hemisphere in which the injection was made, with rescue extending into the inferior hemisphere in many of the eyes. Remarkably, the insertion of a dry needle or injection of PBS into the subretinal space also resulted in widespread photoreceptor rescue, extending through 70% or more of the superior hemisphere, and sometimes into the inferior hemispheres. This implicates the release and widespread diffusion of some endogenous survival-promoting factor from the site of injury in the retina. Our findings indicate that the photoreceptor rescue activity of bFGF is not restricted to inherited retinal dystrophy in the rat, and that light damage is an excellent model for studying the cellular site(s), kinetics, and molecular mechanisms of both the normal function of bFGF and its survival-promoting activity. Moreover, the injury-related rescue suggests that survival-promoting factors are readily available to provide a protective role in case of injury to the retina, presumably comparable to those that mediate the "conditioning lesion" effect in other neuronal systems.

Animals↗
PubMed1992

[Light response of the interphotoreceptor matrix in inherited degenerative retina].

The light-evoked distributional changes of the interphotoreceptor matrix (IPM) in mice with three types of inherited retinal degeneration were examined by histochemistry using fluorescence isocyanate-labeled wheat germ agglutinin. In mice with nervous and Purkinje cell degeneration, the light response of the IPM was still somewhat preserved during the early stage of photoreceptor degeneration, whereas it became extinct when the outer segments (OS) became moderately or markedly shortened. In mice with slow retinal degeneration mice without development of OS, the light response of the IPM was absent throughout the developmental stages. These findings suggest that the presence of normal OS is necessary for the light response of the IPM to occur.

Animals↗
PubMed1991

Development of light-evoked changes of the interphotoreceptor matrix in normal and RCS rats with inherited retinal dystrophy.

The interphotoreceptor matrix (IPM) has recently been shown to undergo a change in distribution following the transition between light and dark [IPM light response: Uehara et al., (1990 b) Science 248, 1633-36]. In the present study, the development of light-evoked IPM changes has been examined histochemically in the retinas of normal and Royal College of Surgeons (RCS) rats with inherited retinal dystrophy between the ages of post-natal day (P) 12 and 40. In normal rats at P12 and P14, the IPM was uniformly and intensely stained with the colloidal iron reaction in both light- and dark-adapted retinas. The capacity of the IPM to undergo the light-evoked distributional change shown previously in adults appeared between P14 and P16. At P16 and older ages, the IPM in light-adapted rats was concentrated in bands at the apical and basal regions of the outer segment zone, whereas the IPM remained uniformly stained in dark-adapted rats. In RCS rats, the light-evoked change developed at the same age as in normal rats, although it was lost between P20 and P25. Correlations of the time of onset and loss (in RCS rats only) of the light-evoked IPM distributional change with other developmental events suggest that mature, organized photoreceptor outer segments are necessary for the IPM light response to occur, and that in RCS rats the disruption of the IPM light response may contribute to the characteristic accumulation of IPM in the basal outer segment zone and photoreceptor cell death in this form of retinal degeneration.

Adaptation, Ocular↗
PubMed1991

[Aging effects on the light response of the interphotoreceptor matrix as revealed by binding of Ricinus communis agglutinin-1].

This study intended to explore whether the light response of the interphotoreceptor matrix (IPM) is affected by aging. The binding pattern of fluorescence-labeled Ricinus communis agglutinin-1 (RCA) to IPM was examined histochemically in 2 month-old and 1.5 year-old rats under light- and dark-adapted conditions. Two month-old animals showed obvious light-evoked changes in the rod associated IPM: the photoreceptor inner segment zone showed a greater fluorescence than the outer segment zone in the light, whereas the staining-intensity of the former was less than that of the latter in the dark. On the other hand, 1.5 year-old rats did not show such light-evoked IPM responses as in 2 month-old animals: no light-dark differences were found in RCA-1 binding. The scarce, linear, preferential binding of RCA-1 to the cone-associated IPM was the same in both lighting conditions independent of the age.

Aging↗
PubMed1991

[Detection of dual phase of light response of interphotoreceptor matrix].

The postnatal development of light-evoked changes in the interphotoreceptor matrix (IPM), a complex of the extracellular matrix that surrounds the photoreceptors and lies between them and the retinal pigment epithelium, was studied by use of a histochemical probe colloidal iron in rats at various postnatal days of age. In the dark, IPM constituents distributed uniformly throughout the outer segment zone and in the apical region of the inner segment zone; this dark pattern of IPM distribution was commonly observed in animals ranging from postnatal day 12 to one year. In the light, little changes were observed at postnatal day 12, followed by varying light-evoked changes in the IPM with increasing ages. At postnatal day 14, the IPM constituents showed a distribution towards the basal region of the inner segment zone along with the dark pattern. At postnatal day 16, they concentrated in bands at the apical and basal region of the outer segment zone, and also in the inner segment zone with expansion from the apical to basal region with increasing time after light exposure. At age one year, the light-adapted IPM constituents were distributed in a manner similar to that on postnatal day 14. The present results confirm the light-evoked changes in the IPM as revealed by colloidal iron-recognized IPM components and provide evidence for postnatal development of the light-evoked changes in the IPM components, whereby the changes appeared earlier and were preserved longer in the basal region of the inner segment.

Adaptation, Ocular↗
PubMed1991

Rod- and cone-associated interphotoreceptor matrix in the rat retina. Differences in light-evoked distributional changes.

Several of the components of the interphotoreceptor matrix (IPM) in the rat have recently been shown to undergo a light-evoked shift in distribution or molecular conformation. In the light, the IPM appears concentrated at the apical surface of the retinal pigment epithelium (RPE) and in the basal outer segment region at the inner and outer segment junction, with relatively little present in the intervening interstitial zone adjacent to the outer segments. By contrast, the IPM in the dark is distributed almost uniformly across the outer segment layer. In the present study, the authors explored whether specialized domains of IPM known as the cone matrix sheaths undergo light-induced changes similar to those previously shown for the IPM as a whole. Fluorescence lectin histochemistry was used on retinal sections of light- and dark-adapted rats with lectins that show selective or preferential binding to cone matrix sheaths, peanut agglutinin (PNA), and Ricinus communis agglutinin (RCA-1). Lectin binding to cone matrix sheaths was the same in both lighting conditions, unlike the rod-associated IPM. These experiments and others using pretreatment of sections with neuraminidase suggested different roles of RCA-1 and PNA-binding components of the IPM in different photoreceptor-RPE cell interactions, including the transfer of substances between the two cell types and retinal adhesion.

Animals↗
PubMed1990

Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor.

Numerous inherited retinal degenerations exist in animals and humans, in which photoreceptors inexplicably degenerate and disappear. In RCS rats with inherited retinal dystrophy, the mutant gene is expressed in the retinal pigment epithelial (RPE) cell, and leads to the loss of photoreceptor cells. Photoreceptors can be rescued from degeneration if they are juxtaposed to wild-type RPE cells in experimental chimaeras or by the transplantation of RPE cells from normal rats. In both cases, the rescue effect extends beyond the immediate boundaries of the normal RPE cells, suggesting trophic action of a diffusible factor(s) from the normal RPE cells. We considered that the fibroblast growth factors, aFGF and bFGF, might have such a trophic role as they are found in the retina and RPE cells; bFGF acts as a neurotrophic agent after axonal injury in several regions of the central nervous system, and bFGF induces retinal regeneration from developing RPE cells. Here we report that subretinal injection of bFGF results in extensive rescue of photoreceptors in RCS rats for at least two months after the injection, and that intravitreal injection of bFGF results in even more widespread rescue, across almost the entire retina. The findings demonstrate for the first time that bFGF can act as a survival-promoting neurotrophic factor in a hereditary neuronal degeneration of the central nervous system.

Animals↗
PubMed1990

Light-evoked changes in the interphotoreceptor matrix.

The normal function of vertebrate photoreceptor cells depends on multiple interactions and transfer of substances between the photoreceptors and the retinal pigment epithelium (RPE), but the mechanisms of these interactions are poorly understood. Many are thought to be mediated by the interphotoreceptor matrix (IPM), a complex extracellular matrix that surrounds the photoreceptors and lies between them and the RPE. Histochemical, immunocytochemical, and lectin probes for several IPM constituents revealed that components of the IPM in the rat undergo a major shift in distribution or molecular conformation after the transition between light and dark. In the light, various IPM constituents concentrated in bands at the apical and basal regions of the outer segment zone; in the dark, they distributed much more uniformly throughout the zone. The change in IPM distribution was triggered by the light-dark transition; it was not a circadian event, and it was not driven by a systemic factor. The light-evoked change in IPM distribution may facilitate the transfer of substances between the photoreceptors and the RPE.

Albinism↗
PubMed1990

Lectin binding of the interphotoreceptor matrix during retinal development in normal and RCS rats.

The retinas of both normal and Royal College of Surgeons (RCS) rats with inherited retinal dystrophy have been examined using lectin histochemistry to determine the developmental and degenerative changes of the glycoconjugates in the interphotoreceptor matrix (IPM) between postnatal day (P) 10 and P25, when the adult lectin binding patterns are seen in normal rats. Wheat germ agglutinin (WGA; recognizing sialic acid and/or N-acetyl-D-glucosamine) bound to the apical surface of the retinal pigment epithelium (RPE) sparsely at P10 and prominently at P12 in both strains. In both strains at P14, WGA also stained the basal outer segment zone at the inner segment-outer segment junction. Between P14 and P16 in both strains, there was a dramatic increase in the binding of the interstitial region, the space alongside the outer segments and between the apical and basal outer segment zones. The binding pattern of WGA in normal rats remained basically unchanged from P16 to P25, although the intensity of binding was increased somewhat. Ricinus communis agglutinin-1 (RCA-1; specific for galactosyl residues) bound to the outer segment zone prominently and diffusely with increasing intensity with age at P10, P12 and P14 in both strains. At P16 and older, the intense binding of the interstitial zone was dramatically reduced and the RCA-1 bound primarily to the inner and outer segment junctional region, with weak binding to the apical surface of the RPE in both strains. At P25, the binding of the inner and outer segment junctional region was even more restricted, limited to punctate sites in this zone in normal rats and almost missing in RCS rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Fine mapping of a putative rd cDNA and its co-segregation with rd expression.

Retinal degeneration is inherited in an autosomal recessive pattern in the retinal degeneration (rd) mouse. The defective gene for this disease has been mapped to mouse chromosome 5 between the well-defined (anchor) genes Afp and Gus. We recently cloned a putative rd cDNA, zr.408, using a strategy based on subtractive and differential hybridization. zr.408 was shown to hybridize to a larger message from rd/rd mice than from normal mice in Northern blots; was mapped to mouse chromosome 5; and was used to detect restriction fragment length polymorphisms (RFLPs) between rd/rd and +/+ DNA in genomic Southern blots. In order to obtain further evidence that zr.408 does in fact correspond to the rd gene, we used two methods to position zr.408 on chromosome 5. Analysis of an intersubspecific backcross localized the sequences corresponding to zr.408 between the genes Afp and Gus, as expected for rd. The second approach involved an interspecific backcross using C57BL/6J-rd/rd mice congenic for the normal allele of rd, which was derived from the wild mouse, Mus spretus; the results of this study showed that zr.408 is at or near the rd locus. These two studies add evidence to the existing data, which suggest that zr.408 is the correspondent of the rd gene.

Animals↗
PubMed1989

Immunogold localization of chondroitin 6-sulfate in the interphotoreceptor matrix of normal and RCS rats.

Localization of chondroitin 6-sulfate (6S) in the interphotoreceptor matrix (IPM) of both normal and RCS rats with inherited retinal dystrophy has been carried out using light and electron microscopic immunogold cytochemistry. In the normal rat, 6S antibody labeling was found in highest concentration at the apical surface of the retinal pigment epithelium (RPE) and between adjacent photoreceptors near their basal inner segment-outer segment junction. In the apical zone, label was localized in the IPM and toward the distal portions of the RPE apical processes. In the basal zone, label was found in the IPM and near the outer plasma membranes of inner and outer segments. Interstitial labeling, between the shafts of outer segments, occurred at much lower concentration than in the apical and basal zones. In all zones, the extent of labeling appeared to be space-dependent; it was most abundant where extracellular spaces were large, and little was present where adjacent cell membranes were contiguous. In the dystrophic rat, apical zone labeling of the RPE apical processes was minimal; instead, the relatively small amount of label that was present was localized primarily in the IPM and within encapsulated spaces of membranous whorls of debris. Label was most concentrated in the basal zone, primarily associated with the IPM within abundant interphotoreceptor spaces, and near the plasma membranes of disorganized inner and outer segments. In isolated eyecups and neural retinas, some labeling persisted after extensive buffer rinses which suggests that chondroitin 6-sulfate is a somewhat insoluble component of the IPM in the rat retina.

Animals↗