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Originally published In Press as doi:10.1167/iovs.08-2206 on September 12, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:242-248.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2206
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Elevated Intraocular Pressure, Optic Nerve Atrophy, and Impaired Retinal Development in ODAG Transgenic Mice

Takaaki Sasaki,1,2 Wataru Watanabe,1,2 Yuki Muranishi,3 Takashi Kanamoto,2 Makoto Aihara,4 Kazuko Miyazaki,1 Hiroki Tamura,2 Tadashiro Saeki,4 Hideaki Oda,5 Nazariy Souchelnytskyi,6 Serhiy Souchelnytskyi,6 Hirohiko Aoyama,7 Zen-ichiro Honda,8 Takahisa Furukawa,3 Hiromu K. Mishima,9 Yoshiaki Kiuchi,2 and Hiroaki Honda1

1From the Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, the 2Departments of Ophthalmology and Visual Science and 7Anatomy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; 3The 4th Department, Osaka Bioscience Institute, Osaka, Japan; the 4Departments of Ophthalmology and 8Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; the 5Department of Pathology, Tokyo Women’s Medical University, Tokyo, Japan; the 6Ludwig Institute for Cancer Research, Uppsala, Sweden; and the 9Hiroshima General Hospital of West Japan Railway Company, Hiroshima, Japan.

PURPOSE. In an earlier study, a cDNA was cloned that showed abundant expression in the eye at postnatal day (P)2 but was downregulated at P10; it was named ODAG (ocular development-associated gene). Its biological function was examined by generating and analyzing transgenic mice overexpressing ODAG (ODAG Tg) in the eye and by identifying ODAG-binding proteins.

METHODS. Transgenic mice were generated by using the mouse Crx promoter. EGFP was designed to be coexpressed with transgenic ODAG, to identify transgene-expressing cells. Overexpression of ODAG was confirmed by Northern and Western blot analysis. IOP was measured with a microneedle technique. The eyes were macroscopically examined and histologically analyzed. EGFP expression was detected by confocal microscope. Proteins associated with ODAG were isolated by pull-down assay in conjugation with mass spectrometry.

RESULTS. Macroscopically, ODAG Tg exhibited gradual protrusion of the eyeballs. The mean IOP of ODAG Tg was significantly higher than that of wild-type (WT) littermates. Histologic analysis exhibited optic nerve atrophy and impaired retinal development in the ODAG Tg eye. EGFP was expressed highly in the presumptive outer nuclear layer and weakly in the presumptive inner nuclear layer in the ODAG Tg retina. Rab6-GTPase-activating protein (Rab6-GAP) and its substrate, Rab6, were identified as ODAG-binding proteins.

CONCLUSIONS. Deregulated expression of ODAG in the eye induces elevated intraocular pressure and optic nerve atrophy and impairs retinal development, possibly by interfering with the Rab6/Rab6-GAP–mediated signaling pathway. These results provide new insights into the mechanisms regulating ocular development, and ODAG Tg would be a novel animal model for human diseases caused by ocular hypertension.






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