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Inside IOVS 2001
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March 2001 |
ANIMAL MODELS: Keys to Understanding Disease Mechanisms
MAP Kinase and Cataract
Transgenic mice with an expression of MAP kinase, MEK1(E), in the lens developed cataracts with enlarged eyes. Studies of these mice by Gong et al. (p. 539) indicate an important role for the MAP kinase signaling pathway in regulating glucose metabolism in the lens and in inducing cataract formation. Identification of novel downstream targets of this signal pathway will allow further understanding of the mechanisms for regulating normal lens formation, maintaining lens transparency and promoting lens opacification. The transgenic mouse may also provide a useful model for understanding the molecular bases for some aspects of human cataracts.
Circadian Rhythms and Eye Growth
The growing eyes of chicks show diurnal rhythms in elongation and in choroidal thickness, the functions of which are unknown. It has been speculated that the phase relationships between these and other ocular rhythms might influence ocular growth rate and thereby influence the refractive state of the eye. Nickla et al. (p. 584) show that the rhythms in axial length and choroid thickness are endogenous circadian rhythms, as they persist in constant darkness. The authors speculate on the implications for ocular growth regulation with respect to the effects of pattern vision on these rhythms.
Opsin Expression and Retinal Degeneration
When normal opsin is over-expressed in the retina of transgenic animals, it causes a photoreceptor degeneration resembling that observed with expression of mutant opsin. Tan et al. (p. 589) assessed the correlation between the level of opsin over-expression and the severity of retinal degeneration. Degeneration was induced by opsin levels that exceed those found normally by only ~23%. Analysis of retinaldehyde levels revealed that the retina has a limited capacity to increase the available supply of rhodopsin’s chromophore in response to opsin over-expression. The potential implications of opsin over-expression with regard to retinitis pigmentosa are discussed.
Mucin and Conjunctivitis
Morphometric analysis of conjunctival epithelium in a canine keratoconjunctivitis sicca (KCS) model by Moore et al. (p. 653) revealed restoration of depleted mucin stores following topical cyclosporine (CsA) treatment. Stimulation of conjunctival goblet cell mucin production, i.e., the balance between synthesis and secretion of mucin glycoproteins, may play an important role in the beneficial effects of CsA in treating KCS. The degree of conjunctivitis and severity of mucus discharge were decreased in KCS eyes treated with CsA. Future strategies for dry eye therapy may include manipulation of quantitative and qualitative secretory events of the conjunctival mucus system.
Myo7a and Usher Syndrome
In humans, mutations in the gene encoding myosin VIIa causes Usher syndrome type 1B (USH1B), which is characterized by congenital deafness and the early onset of retinitis pigmentosa. However, it is unclear why the survival of the photoreceptors depends on myosin VIIa. While there are mice with mutations in the myosin VIIa gene (shaker1 mice), their retinas do not degenerate. Libby and Steel (p. 770) analyzed the retinas of shaker1 (sh1) mice to determine if they respond normally to light. The authors found that the sh1 mouse has attenuated responses to light. Thus, the sh1 mouse may be a model system to study the early stages of USH1B.
Opsin Mutations and RP Phenotypes
Rhodopsin mutations account for many adRP cases of known genetic etiology. To evaluate the relative contributions of normal and mutant proteins to the disease process, mice with a mutant rhodopsin transgene were mated to rhodopsin knockout mice to generate offspring expressing the mutant rhodopsin on backgrounds of two, one or zero normal alleles. Analysis of all six possible genotypes by Frederick et al. (p. 826) support the use of this system to correlate the presence of specific mutations in the rhodopsin gene with features of retinopathy, e.g., time of onset, rate of progression, intracellular fates of mutant vs. normal protein and extent of rod photoreceptor degeneration.
Methanol and Photoreceptor Toxicity
Studies in a rodent model of methanol toxicity by Seme et al. (p. 834) demonstrate that methanol-derived formate inhibited retinal energy metabolism, increased oxidative stress and profoundly attenuated retinal function. Animals allowed to recover from methanol intoxication exhibited a partial recovery of rod-dominated responses and no recovery of UV-cone-mediated responses, indicative of a differential sensitivity of photoreceptors to the cytotoxic actions of formic acid. Studies of formate-induced retinal dysfunction may provide valuable insight into the pathogenesis of other acquired and genetic retinal disorders.
nrc Visual Behavioral Mutants
Zebrafish mutants serve as useful models for human retinal disorders. Van Epps et al. (p. 868) describe the physiology and genetic map position of the zebrafish visual mutant no optokinetic response c (nrc). The nrc electroretinogram phenotype is consistent with both abnormal synaptic transmission and abnormal photoreceptor light adaptation. The nrc mutant retinal phenotype shows striking similarities with phenotypes of dystrophin glycoprotein complex mutants. Some mutations in the dystrophin glycoprotein complex and associated proteins cause Duchenne/Becker Muscular Dystrophy. Determination of the nrc map position is the first step in identifying the gene mutated in this novel zebrafish retinal mutant.
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