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S.I. Tomarev, A.S. Kraev, Y. Zhou; Changes in the Gene Expression Patterns in the Eyes of Mice With Open–Angle Glaucoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5448.
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© ARVO (1962-2015); The Authors (2016-present)
Previously we reported the development of a novel transgenic mouse model of glaucoma by the expression of mutated (Tyr423His) mouse myocilin (Myoc) (ARVO 2005, abstract # 2371). This mutation corresponds to the Tyr437His mutation in the human MYOC gene. Here we investigate changes in the gene expression patterns in different eye tissues of transgenic (TG) animals as compared with their wild–type (WT) littermates.
Total RNA was isolated from the retina, combined trabecular meshwork/ ciliary body, and combined RPE/choroid/sclera of 5 and 12 month old WT and TG mice. Isolated RNA was amplified by a T7 RNA polymerase–based procedure and cRNA was labeled with Alexa Fluor 555 and 647. Labeled cRNA was used in hybridization experiments with Agilent mouse 44K microarrays. The results of microarray hybridization were analyzed using web–based microarray analysis tools at the NIA/NIH. Changes in the levels of selected mRNAs were confirmed by real–time PCR.
Similar to WT Myoc, mutated Myoc was expressed in tissues of the irido–corneal angle and RPE/choroid/sclera. Expression of mutated Myoc in these tissues induced up–regulation of several genes including those encoding prostaglandin D2 synthase, glutathione transferase omega, keratin (Krt2–5), phosphatidylinositol glycan, class T, glucose transporter 1, CCAAT/enhancer binding protein zeta (Cebpz), and gap junction membrane channel protein alpha 4. The list of down–regulated genes included those encoding extracellular protein asporin, anti–proliferative (Btg2), membrane–spanning 4–domains, subfamily A, member 6D, and adhesion and degranulation–promoting adapter protein (ADAP). A group of genes up–regulated in the retina included those encoding nitric oxide synthase 1, midkine, heat shock protein 1, insulin receptor substrate 4, as well as several proteins highly expressed in photoreceptors (peripherin, phosducin, rod outer segment membrane protein 1). Genes encoding galactose–4–epimerase, ferritin heavy chain, F–box protein 39, and plasmalemma vesicle associated protein were up–regulated in all analyzed tissues.
Expression of mutated mouse Myoc in the eyes of TG animals induced changes in the gene expression patterns in all analyzed tissue before any morphological abnormalities could be detected. Some of these changes have been previously reported in glaucoma in humans or in other animal models of glaucoma, while other changes are reported here for the first time.
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