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The Journal of Neuroscience, November 15, 2006, 26(46):11903-11914; doi:10.1523/JNEUROSCI.3020-06.2006

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Neurobiology of Disease
Expression of Mutated Mouse Myocilin Induces Open-Angle Glaucoma in Transgenic Mice

Vladimir Senatorov,¹ Irina Malyukova,¹ Robert Fariss,² Eric F. Wawrousek,¹ Srividya Swaminathan,³ Shyam K. Sharan,³ and Stanislav Tomarev¹

¹Section of Molecular Mechanisms of Glaucoma, Laboratory of Molecular and Developmental Biology, and ²Biological Imaging Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, and ³Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland 21702

Correspondence should be addressed to Dr. Stanislav Tomarev, National Eye Institute, National Institutes of Health, Building 7, Room 103, 7 Memorial Drive, MSC 0704, Bethesda, MD 20892-0704. Email: tomarevs{at}nei.nih

We developed a genetic mouse model of open-angle glaucoma by expression of mutated mouse myocilin (Myoc) in transgenic (Tg) mice. The Tyr423His point mutation, corresponding to the severe glaucoma-causing Tyr437His mutation in the human MYOC gene, was introduced into bacterial artificial chromosome DNA encoding the full-length mouse Myoc gene and long flanking regions. Both wild-type (Wt) and Tg animals expressed Myoc in tissues of the irido-corneal angle and the sclera. Expression of mutated Myoc induced the accumulation of Myoc in cell cytoplasm and prevented its secretion into the extracellular space. The levels of ATPase-1 were reduced in the irido-corneal angle of Tg mice compared with Wt animals. Tg mice demonstrated a moderate elevation of intraocular pressure, the loss of 20% of the retinal ganglion cells (RGCs) in the peripheral retina, and axonal degeneration in the optic nerve. RGC depletion was associated with the shrinkage of their nuclei and DNA fragmentation in the peripheral retina. Pathological changes observed in the eyes of Tg mice are similar to those observed in glaucoma patients.

Key words: glaucoma; myocilin; transgenic mice; trabecular meshwork; retina; retinal ganglion cells

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Received July 17, 2006; revised Sept. 12, 2006; accepted Sept. 29, 2006.

Correspondence should be addressed to Dr. Stanislav Tomarev, National Eye Institute, National Institutes of Health, Building 7, Room 103, 7 Memorial Drive, MSC 0704, Bethesda, MD 20892-0704. Email: tomarevs{at}nei.nih

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