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W. Cao, I. Dozmorov, R. Knapp, Y. Zhu, M. Frank, S. Li, C. Soliman, M. Centola, F. Li; Differential Gene Expression in the Retinas of tubby Mice: A cDNA Microarray Analysis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4748.
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© ARVO (1962-2015); The Authors (2016-present)
The homozygous tubby mutant mouse has an early progressive hearing loss and progressive photoreceptor degeneration, the two phenotypic hallmarks of Usher syndrome type I seen in humans. Therefore, tubby mouse has been described as a phenotypic model of this human inherited disease. The mechanism(s) underlying neuronal degeneration in this disease are unknown. The aim of this study is to identify differentially expressed genes that may relate to photoreceptor degeneration in the retinas of tubby mice during postnatal period.
Breeding pairs of tubby mice were obtained from Jackson Laboratory. The retinas of tub/tub and tub/+ mice were dissected. Total RNAs were isolated and DNA microarrays were performed using a mouse genomic oligo set representing 17,600 genes. Differentially expressed genes were identified using associative analysis. Robust regression analysis, correlation coefficient analysis, F–means cluster analysis and Discriminant Function Analysis were used for second–stage analysis of the differentially expressed genes. Quantitative real–time PCR, semi–quantitative reverse transcriptional (RT) PCR and Western blot analysis were used to confirm some of differential expressed genes.
Our data showed that a group of photoreceptor specific genes, including interphotoreceptor matrix proteoglycan–1 (IMPG1), photoreceptor cadherin, and retinal outer segment membrane protein 1(ROM1) was significantly down–regulated at early postnatal period (P10–14) before significant photoreceptor degeneration occurred. Interestingly, a group of anti–oxidant enzymes encoding genes, such as thioredoxin (Trx) and thioredoxin reductase (TrxR), and survival/growth factors (BNDF, GDNF, FGF–3) was significantly down–regulated during this period. Some other down–regulated genes were related to cell survival, signaling and transcription, such as cAMP response element binding protein (CREB), and inhibition of apoptosis. Furthermore, a group of genes related to apoptosis (Bak–1, capspase–2, –3, –8 and –9 and TNFR supfamily, member 11b) was significantly increased in the retinas of tubby mice. The altered expressions of IMPG1, ROM1, CREB, Trx and TrxR were further confirmed by real–time PCR and RT–PCR as well as by western blot analysis.
Loss–of–function mutation of tubby gene leading to down–regulation of a group of genes related to cell survival may cause photoreceptor degeneration in the retinas of tubby mice.
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