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| December 2007 | Inside IOVS | Volume 48/12 |
Pax6 Overexpression Inhibits Mitosis Progression
Zaccarini et al. (p. 5408) present results suggesting that Pax6 protein is localized to chromosomes, predominantly in a pericentromeric area, and overexpression of the Pax6/p46 protein induces a mitosis defect through its interaction with separase, an enzyme required for chromatid separation. Because of its long 12-hour half-life and particular chromosomal location, Pax6 may be an internal clock measuring the mitosis number. As soon as a critical threshold of p46 is reached on the chromosome, mitosis is no longer possible, and differentiation may occur. This may also explain why Pax6 behaves as an anti oncogene, in contrast to the other Pax genes.
A Key Role for Calpains in Retinal Ganglion Cell Death
Apoptosis, or programmed cell death, is known to occur in retinal ganglion cell (RGC) degeneration in such conditions as glaucoma. The majority of work in this field has focused on caspase as being the key executioner. However, McKernan et al. (p. 5420) provide evidence in both in vitro and ex vivo models of RGC death that the calpain proteases may play an important role. These results suggest that certain calpain inhibitors may be effective in preventing cell death execution.
Retinal Gene Expression in Rat Glaucoma and Optic Nerve Axotomy
Investigation of the molecular mechanisms underlying retinal ganglion cell (RGC) degeneration in glaucoma is of great importance in the development of novel diagnostic and therapeutic strategies. Yang et al. (p. 5539) directly compared retinal gene expression alterations in a rat glaucoma model and after optic nerve axotomy, identifying genes that were commonly and differentially implicated in the pathogenesis of RGC death in these two distinct but related RGC damage models. Their findings suggest that both protective and detrimental processes take place in damaged RGCs and support the involvement of neuroinflammation and TNF-a pathways in glaucomatous RGC degeneration.
Th-1 and Th-2 Mechanisms Can Both Produce Lacrimal Gland Inflammation
MRL/MpJ mice are a model for the human disorder Sjögren's Syndrome. In MRL/MpJ mice the disease appears to be predominantly Th2-mediated. IL-4 is a cytokine which plays a key role in the Th2 response. Jabs et al. (p. 5624) bred MRL/MpJ mice with a mutation in the IL-4 gene producing a functional IL-4 knockout. These mice developed lacrimal gland disease as severe as those seen in mice with an intact IL-4 gene, which, however, appeared to be Th1 in nature. These data suggest that both immunologic mechanisms can produce lacrimal gland inflammation, depending on the cytokine repertoire available.
Transformation of Normal Capillaries to VEGF-Dependent Vessels
Using a novel model of retinal neovascularization in rabbits, Ameri et al. (p. 5708) found that normal capillaries could transform to vascular endothelial growth factor (VEGF)-dependent vessels following acute exposure to a high dose of VEGF. This phenomenon may be used to sensitize established neovascular membranes or established vessels in ocular or systemic tumors to anti-VEGF drugs. The study may in particular lead to novel therapeutic measures for systemic cancers.
Inflammatory Cytokines PDGF-C and -D Induce Human RPE Proliferation
PDGF-C and -D are the major isoforms expressed in human RPE. Functionally active PDGFR-a and -b are mainly expressed at the apical membrane. PDGF-BB, -CC, and -DD significantly increased proliferation while PDGF-BB, -AB, and -DD significantly increased cell migration, suggesting a critical role in RPE pathophysiology. A pro-inflammatory cytokine mixture (TNFa/IL-1b/IFNg) abrogated PDGF-induced proliferation and migration by inducing apoptosis and by disrupting the cytoskeleton and tight junctions. Surprisingly, this mixture stimulated the proliferation of choroidal cells. These findings, reported by Li et al. (p. 5722), suggest an important role of pro-inflammatory cytokines in overcoming local proliferative/wound healing responses at the retina/RPE/choroid interface.
CNTF: Effects on Vision and the ERG
CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. McGill et al. (p. 5756) show here that in normal adult rats, very high doses of CNTF injected intravitreally, or subretinal delivery of adeno-associated virus-vectored CNTF, result in the reduction in ERG amplitudes accompanied by a reduction in vision. Vision was assessed by determining the spatial frequency thresholds of the optokinetic response (OKR) and the visual water task. High doses of CNTF also resulted in elevation of multiunit luminance thresholds recorded in the superior colliculus. However, dose-response analysis of ERG responses and the OKR compared with a dose-response study of protection from light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses.
Priming Approach to Probe Metaplasticity of Human Visual Cortex
According to the Bienenstock-Cooper-Munro (BCM) model, a "sliding modification threshold" controls the level for inducing synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). Lang et al. (p. 5782) now demonstrate an approach to probe a BCM-like type of metaplasticity with combined transcranial stimulation techniques of human visual cortex. Their results suggest that, compared to previous work on motor cortex, the priming effects of visual cortex are relatively modest and point to substantial differences in the modifiability of different cortices. However, their method appears a promising approach for testing visual cortex metaplasticity in health and disease.
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