Cataract- and lens-specific upregulation of ARK receptor tyrosine kinase in Emory mouse cataract.

The Emory mouse is a well-characterized model for age-onset cataract.1 Two substrains of Emory mice in which cataracts develop at 5 to 6 months (early-cataract strain) and 6 to 8 months (late-cataract strain) are known.1 Emory mouse cataracts increase in severity with age and first develop in the anterior superficial cortex region of the lens.2 They eventually progress into the anterior deep cortex region and ultimately result in complete lens opacification.2 Emory mouse cataracts are also associated with numerous lens changes that appear to mimic accelerated aging. These include abnormal lens growth; decreased protein accumulation; conversion of soluble to insoluble protein; decreased glutathione and protein sulfhydryl levels1; increased sodium and water content3; decreased superoxide dismutase, catalase, glutathione peroxidase,4 and γ-glutamylcysteine synthetase5 activities; and accelerated conversion of MIP-26 to MIP-24.6 The Emory mouse is associated with changes in crystallin composition, including covalent changes in α-crystallin7 and decreased levels of β- and γ-crystallin proteins.1 Levels of mRNA encoding αA-crystallin, βB1-crystallin, γ-crystallin, al-dose reductase, and especially MIP-26 are decreased8 in Emory mouse cataract in comparison with control lenses, indicating that altered expression of genes is associated with aging and cataract in the Emory mouse. The present study sought to further identify specific genes with expression levels that are altered between pre- and post-cataract Emory mouse lenses. Reverse transcription-PCR differential display was used, as previously described for human lenses.9 Using this approach, we confirmed results in a previous study demonstrating decreased expression of αA-crystallin8 and identified two new genes exhibiting altered gene expression in Emory mouse cataract, including βA3/A1-crystallin (decreased) and ARK receptor tyrosine kinase (increased). Crystallins make up more than 90% of the water-soluble protein of the mammalian eye lens, where they are critical for lens transparency and refraction. In the vertebrate eye lens, three major classes of ubiquitous crystallins are found: α-, β-, and γ-crystallins.10,11 The β- and γ-crystallins have a common polypeptide chain fold, share conserved sequences, and together form a superfamily of βγ-crystallins.12 In contrast, the α-crystallins form a separate family of proteins related to small heat-shock proteins.13 αA-crystallin is a molecular chaperone,14 with properties consistent with its having an important role in the maintenance of lens transparency. Adhesion-related kinase (ARK) is associated with cell adhesion,15,16 and its activating ligand has been identified as the growth arrest–specific gene Gas6, which is upregulated in serum-starved fibroblast cell lines.17,18 Expression of ARK has been previously localized to nervous tissues.16 The human homologue of ARK, AXL-UFO, has been identified.19,20 The present data demonstrate lens- and aging-specific changes in the gene expression levels of ARK receptor tyrosine kinase, αA-crystallin, and βA3/A1-crystallin in the Emory mouse. The results support the hypothesis that specific gene expression changes are associated with Emory mouse cataract and associate the functions of the identified genes with the maintenance of lens transparency.