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| February 2004 | Inside IOVS | Volume 45/2 |
Delayed Expression of Crx Causes Abnormal Photoreceptor Development in the Chx10-Deficient Mouse
Lack of the transcription factor Chx10 causes microphthalmia in humans and in mice. Rutherford et al. (p. 375) examined how neuronal development is affected by lack of Chx10. They found that expression of the photoreceptor gene Crx, and targets of Crx regulation were delayed in their onset of expression. Delay of the normal temporal expression of genes essential for photoreceptor disc morphogenesis appears to cause the failure of correct rod and cone outer segment formation in the mutant retina. This study indicates the critical role that coordinated expression of multiple transcription factors play in development of the neural retina.
PAX6 Human Mutations in Relation to Ocular Disease
Pax6 plays an important role in the development of the eye, central nervous system and pancreas, and is involved in the etiology of congenital ocular diseases. Chauhan et al. (p. 385) examined properties of ten representative PAX6 and PAX6(5a) human mutations. Their data show differential transactivation effects of specific mutations depending on the location of the mutation, DNA-binding mechanism and, importantly, cellular environment. Their study provides insight into how different mutations in PAX6 and PAX6(5a) could produce the spectrum of phenotypes in vivo.
Postnatal Gene Expression Changes in Mouse Cornea Demonstrated by SAGE
Serial Analysis of Gene Expression (SAGE) is a powerful method using sequence tags to identify both known and unknown expressed genes in any tissue. Norman et al. (p. 429) have used SAGE to identify at least 19,544 and 18,509 genes in the mouse cornea at postnatal day 9 and in the adult, respectively. Only one-third of the expressed genes overlapped at the two developmental stages. These results demonstrate surprisingly dynamic changes in gene expression in the postnatal cornea and provide a molecular genetic foundation for further studies on the normal and diseased mouse cornea.
Structural and Molecular Heterogeneity in Resting Limbal Vessels
Mouse strain-specific regulation of corneal gene expression may influence the vascular pattern of the resting limbus and its susceptibility to angiogenic stimuli. Chan et al. (p. 441) demonstrate increased limbal vessel surface area and density in naïve adult 129S3/SvIM compared to C57BL/6J mice and correlate this with strain-related differences in resting corneal gene expression. The mouse strain with higher levels of limbal vascular density showed a greater corneal angiogenic response to bFGF. Thus, strain-specific corneal gene expression profiles may influence vascular phenotype during quiescence and may potentially predict susceptibility to angiogenesis-dependent disease.
Connective Tissue Growth Factor, TGF-b, and Bleb Failure Following Glaucoma Surgery
Subconjunctival scarring following glaucoma filtration surgery (GFS) is responsible for failure of the surgery in the majority of cases. Esson et al. (p. 485) present data that support the hypothesis that connective tissue growth factor (CTGF – a downstream mediator of transforming growth factor-b) plays a role in this scarring process. CTGF and its activation genes may provide another target for limiting GFS failure. CTGF expression was localized to the site of surgery and varied significantly with the type of GFS performed.
Efficacy of DNA vs. Protein Immunization
This study compared the effectiveness of immunization with "naked" DNA, corresponding to the genes encoding the 5 HSV-1 glycoproteins, gB, gC, gD, gE, and gI, with that of a vaccine containing the 5 glycoproteins. Osorio et al. (p. 506) found that mice immunized with DNA had less ocular virus replication, blepharitis, and latency than mice immunized with the protein vaccine. In addition, mice vaccinated with DNA had higher levels of IL-12 and IFN-g than the protein vaccines. Furthermore, the authors observed no advantage in using protein primed-DNA boosted or DNA primed-protein boosted immunizations compared with DNA primed-DNA boosted immunization. Their results suggest that the DNA vaccine is more effective against ocular HSV-1 infection than the corresponding protein subunit vaccine.
Retinal Hypoxia and Diabetic Macular Edema
The pathogenesis of diabetic macular edema (DME) and the mechanism by which focal and grid laser photocoagulation provide benefit are poorly understood. While direct closure of microaneurysms may play a role, it is also possible that laser photocoagulation to areas of macular thickening acts in part by decreasing oxygen demand by the outer retina and increasing oxygen supply to the inner retina. This would imply that retinal hypoxia plays an important role in the pathogenesis of DME. Nguyen et al. (p. 617) provide direct evidence that this is the case. Five consecutive patients with DME, who had persistent macular thickening despite focal and grid laser photocoagulation and no improvement for at least 3 months after their last laser treatment, were given continuous supplemental oxygen (4 liters/minute by nasal cannula). After 3 months of treatment, 9 of 9 eyes with DME at baseline had reduction in thickness of the center of the macula as assessed by OCT. Three different OCT parameters indicated reduction in excess thickening by an average of more than 40%. Three eyes showed improvement in VA by at least 2 lines, one by slightly less than 2 lines, and 5 eyes showed no change. Three months after stopping oxygen, these gains were lost in 5 of the 9 eyes, but remarkably, 4 eyes showed persistent benefit after oxygen had been stopped. An intriguing possibility is that severe macular thickening in these four eyes prevented improvement from focal and grid laser photocoagulation, but once retinal thickening was decreased, benefits from laser were unmasked.
PDZ Domains and the Visual Cycle
Nawrot et al. (p. 393) demonstrate that cellular retinaldehyde-binding protein (CRALBP), which is indispensable for efficient function of the rod and cone visual cycles, interacts directly with the two PDZ-domains of ERM-binding phosphoprotein 50 (EBP50) and indirectly with the actin-binding, ERM protein ezrin. All three proteins and actin are present in apical processes of RPE and Müller cells. EBP 50 is required for an apical localization of specific proteins in other tissues, but has not previously been associated with the visual cycle. The results here suggest that EBP50 may be a scaffold for the assembly of a retinoid-processing complex in apical processes of RPE and Müller cells.
Quantitation of Corneal Nerve Fiber Damage by Confocal Microscopy
The accurate quantification of small nerve fiber damage, especially in diabetic polyneuropathy, is important. Corneal confocal microscopy is a reiterative, rapid, non-invasive in-vivo clinical examination technique capable of imaging corneal nerve fibers. Kallinikos et al. (p. 418) have applied a novel mathematical paradigm to quantify and relate the extent of corneal nerve tortuosity to increasing severity of somatic neuropathy in diabetic patients. This may be useful for future studies in diabetic patients as it may indicate a degenerative and attempted regenerative response of nerve fibers and may also help define at risk patients, anticipate deterioration, and assess the efficacy of new therapies.
Recovery of Macular Function Following Macular Translocation Surgery
Macular translocation surgery was performed on patients with age-related macular degeneration with subfoveal choroidal neovascularization to move the fovea from diseased RPE to healthier RPE. The questions asked were: does the newly located retina-RPE complex function as well as the original macula, and is the recovered function long-lasting? Terasaki et al. (p. 567) used focal macular ERGs to demonstrate that the macular function was partially recoverable in the early postoperative period and continued to improve with longer follow-up time. The properties of the preoperative focal macular ERG, but not the visual acuity, had some predictive value on the postoperative visual acuity.
Oxidative Stress and RPE
Oxidative stress has been implicated in several forms of retinal dystrophy. Bailey et al. (p. 675) examined the response of RPE cells in culture to oxidative stress. They found that ARPE-19 cells became more resistant to chronic oxidative stress with increased time in culture, which correlated with differentiation and increased basal levels of heat shock proteins and differential responses to stress. Sub-lethal chronic oxidative stress disrupted tight junction and adherens junction protein organization and increased paracellular flux. Such a disruption in vivo would have important implications for the maintenance of the blood retinal barrier and RPE cell proliferation in diseases where chronic oxidative stress occurs.
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