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| October 2003 | Inside IOVS | Volume 44/10 |
RP1 is Required for OS Organization
Truncation mutations in the RP1 gene are a common cause of dominant retinitis pigmentosa. Liu et al. (p. 4171) found that the mutant RP1 mRNA is present in lymphoblasts from RP1 patients, suggesting that a truncated protein is produced in the retina. The authors then used gene targeting techniques to generate Rp1-myc mice that produce a truncated Rp1 protein in their retinas. Mice homozygous for the mutant Rp1-myc allele undergo a rapid retinal degeneration, characterized by the production of short stacks of misoriented discs in photoreceptor outer segments. The truncated protein appears not to exert a dominant negative effect in heterozygous mice. The RP1 protein thus appears to be required for the correct orientation and higher order stacking of outer segment discs.
Chlamydial Infection Load in Trachoma
The effective use of antibiotics in trachoma control programs depends on delivering treatment to infected individuals. However, many infected individuals do not have clinical signs of disease. Burton et al. (p. 4215) measured the chlamydial infection load in all members of an endemic Gambian community by quantitative PCR. Many infected individuals were clinically normal while having high loads of chlamydial infection. If such individuals do not receive treatment, then antibiotics for trachoma control may have a limited effect. Antibiotic distribution strategies need to include the treatment of clinically normal people who live in close proximity to those with disease to successfully target infection.
Binocular Vision with Primary Microstrabismus
It is commonly assumed that primary microstrabismus is a unique binocular disorder caused by innate anomalies in sensory, retinal disparity mechanisms. To investigate the potential etiology, Harwerth and Fredenburg (p. 4293) compared the properties of sensory and motor fusion in orthotropic and microstrabismic subjects. They did not find evidence of a specific sensory abnormality as a cause of the small ocular deviation, but rather, that primary microstrabismus represents a highly adapted state of binocular vision, with stable eye alignment, and normal disparity vergence and coarse depth perception based on harmonious anomalous retinal correspondence. The results of the studies support the concept that the sensory characteristics of microstrabismus are a consequence of early abnormal visual experience, just as in large-angle strabismus.
Neurotrophic Gene Therapy for Glaucoma
At present, the only treatment proven to slow the loss of retinal ganglion cells (RGC) in human glaucoma is the lowering of eye pressure. Additional promising approaches to protecting RGC target pathogenic steps in the apoptosis pathway. Martin et al. (p. 4357) delivered the human gene for brain-derived neurotrophic factor to RGC with an adeno-associated viral vector by intravitreal injection. Significant protection against RGC loss in a rat glaucoma model was proven after several weeks of exposure to high eye pressure. This experiment shows that experimental protection of RGC in glaucoma can be achieved through delivery of neurotrophins, in this case by gene therapy.
PI-3K Signaling during Lens Cell Proliferation and Differentiation
Signaling mechanisms involved in lens cell proliferation and differentiation promoted by individual growth factors can be different. Chandrasekher and Sailaja (p. 4400) demonstrate that regulation of PI-3K/Akt activation is critical in these cellular processes mediated by some growth factors. Inhibition of PI-3K activation blocks epithelial cell proliferation but enhances the synthesis of d-crystallin, an early differentiation marker protein. There are significant differences in the modulation of PI-3K/Akt signaling by insulin, IGF-1, FGF-2 and PDGF during proliferation and differentiation of lens cells. Cross-communication between signaling pathways activated by growth factors appears to be key for the effective regulation of these cellular processes.
Drusen Induce Focal Retinal Degeneration
Drusen accumulation is regarded as a hallmark sign of ocular aging and age-related macular degeneration (AMD). Some have proposed that drusen are indirectly responsible for the loss of vision associated with the atrophic form of AMD. Johnson et al. (p. 4481) demonstrated that drusen exert localized degenerative effects upon the overlying neural retina, including the loss of photoreceptor synaptic machinery and other photoreceptor-related defects. Such effects are associated with large drusen and smaller, subclinical drusen, thus suggesting that drusen formation is accompanied by focal injury to the retina that begins long before vision loss is evident clinically.
ICG Lights up Reticulocytes
Indocyanine green (ICG) is a well-known dye for ophthalmic angiography. Less well-known is the fact that ICG is taken up by certain circulating cells following dye clearance from the plasma. It has been suggested previously that these cells are leukocytes and ICG can be used to track leukocytes in vivo. By examining the in vivo trafficking pattern of ICG-labeled cells and the profiles of in vitro immunofluorescence labeling, Wei et al. (p. 4489) discovered that ICG labels reticulocytes instead of leukocytes. Consequently, ICG may be a useful probe for imaging reticulocyte-releated disorders, such as sickle cell retinopathy.
Retinal Neuroprotection against Ischemic Injury by PEDF Ad Vector
Pigment epithelium-derived factor (PEDF) has been shown to be a retinal neurotrophic factor and also an antiangiogenic factor for retinochoroidal neovascularization. Currently, a phase 1 clinical trial evaluating PEDF expressing vector with choroidal neovascularization is enrolling patients. Takita et al. (p. 4497) examined whether gene transfer approaches may be extended to include retinal neuroprotection. PEDF expressing adenoviral vector significantly increases cell survival following ischemia reperfusion insult. The protective effect may result from inhibition of ischemia-induced apoptosis. This study provides proof of concept for a gene transfer approach directed at interrupting programmed cell death induced by retinal ischemic insult.
Transcription Factors HIF-1 and NF-kB and Retinal Neovascularization
Retinal neovascularization (NV) is coordinated by a family of genes that include vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Lukiw et al. (p. 4163) have analyzed the binding of transcription factors HIF-1 and NF-kB to DNA in relation to VEGF and COX-2 gene expression in IL-1b or hypoxia-triggered monkey retinal endothelial cells. Encoding the rate-limiting oxygenase in inducible prostaglandin (PG) biosynthesis, COX-2 generates PGs which induce VEGF. The carboxamide CGP43182, via repression of NF-kB-driven target gene activation, also suppresses COX-2 and VEGF expression. Data indicate that VEGF expression may be up-regulated through two interdependent mechanisms, one directly via HIF-1-VEGF promoter activation and one indirectly through NF-kB-mediated COX-2 expression and VEGF induction by PG.
Cellular Function of Nyctalopin
Mutations in the gene encoding nyctalopin (NYX) lead to a retinal dysfunction designated complete congenital stationary night blindness (CSNB1). The protein is a member of the leucine-rich repeat superfamily but its function is yet unknown. Zeitz et al. (p. 4184) have characterized experimentally protein motifs of human and mouse nyctalopin and show that it is directional transported intracellularly and attached to the outer plasma membrane of cells. Disease associated mutations do not alter the protein transport or membrane localization. Their findings lead the authors to speculate that NYX may play an important role in cell contact and interaction processes in the human and mouse retina which is disturbed in patients with CSNB1.
Splicing Factor Expression Modulates Disease for Dominant RP (RP11)
In all autosomal dominant retinitis pigmentosa families with PRPF31 mutations, the disease gene carriers are either severely affected or asymptomatic. Vithana et al. (p. 4204) have demonstrated that the most probable reason for this "all or none" phenotype is the different levels of expression of the normal copy of the gene that is able (or unable in symptomatic individuals) to compensate for lack of or non-functional gene product, due to mutations. Identification of the genetic cause of differential expression of PRPF31 gene will enable accurate prognosis of disease progression in pre-symptomatic children from carrier parents. Furthermore a potential avenue for future therapy has been revealed, as moderate over-expression of wild type PRPF31 may prevent clinical manifestation of the disease.
Advanced Glycation Endproducts (AGEs) as a Modulator of Retinal Leukostasis
The role of AGEs in the pathogenesis of diabetic retinopathy remains ill defined. Moore et al. (p. 4457) have demonstrated a link between high circulating levels of AGEs (known to occur in diabetic patients) and the adherence of leukocytes with the retinal microvasculature (leukostasis). Using evidence drawn from a range of in vitro and in vivo approaches, the study presents evidence for AGE-mediated activation of the retinal microvascular endothelium to express ICAM-1, via an NF-kB pathway, leading to capillary leukocyte adherence and associated compromise of the blood retinal barrier. Appropriate prevention of AGE-mediated pathways may help to limit microvascular dysfunction during diabetic retinopathy.
Cryptochrome and Non-Visual Photoreceptive Functions
In addition to processing complex visual information, the human retina participates in nonvisual photoreceptive functions, including pupillary constriction and resetting the circadian clock. Cryptochrome is a candidate photopigment for mediating these tasks, and here, Thompson et al. (p. 4515) demonstrate that of two human cryptochrome homologs, CRY2 is highly expressed in ganglion cells of the human retina. The cytoplasmic localization of CRY2 observed in the retina contrasts with its nuclear localization reported in the mouse brain. This suggests pleiomorphic roles for cryptochrome: a cytoplasmic, photoreceptive function in retina and a nuclear, light-independent, regulatory role in the transcriptional feedback loop governing circadian rhythms.
Photoreceptor Sensitivity and Circadian Signals
Melatonin is produced at nighttime in photoreceptors under the control of an endogenous circadian oscillator. It has been long known that melatonin binds to target cells in the inner retina to influence photoreceptor function, but it has been just recently discovered that the photoreceptor cells themselves may be direct targets of melatonin circadian signaling. Wiechmann et al. (p. 4522) have demonstrated that transgenic frogs that over-express melatonin receptors display increased sensitivity to light stimuli. These data provide evidence that retinal photoreceptors are directly responsive to melatonin, and may represent an important mechanism by which circadian signals affect retinal function.
FGF2 and EGF Promote Photoreceptor Cell Survival
Analysis of neurotrophic factors for potential survival-stimulating effects against photoreceptor death have principally been performed either in vivo in rodent models, or in vitro in neonatal cell cultures. In either case, extrapolation to human retinas is not straightforward. Traverso et al. (p. 4550) describe a novel method for preparing almost pure rod and cone photoreceptor cultures from adult pig retinas. Addition of exogenous FGF2 or EGF were found to improve cell survival and stimulate expression of key proteins in vitro. Hence these data suggest the potential therapeutic interest of FGF2 and EGF to limit photoreceptor loss.
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