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 pulldown 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. (Invest Ophthalmol Vis Sci. 2009;50:242-248) DOI:10.1167/iovs.08-2206 O cular development is a complex process, involving several genes with expression that is strictly controlled in a spatial and temporal manner. Although several genes, including Pax6, Rx, and Crx, are essential for normal ocular formation, 1-3 the molecular mechanism(s) governing eye development has not been fully elucidated. To identify genes that are preferentially expressed in the developing eye, we performed a differential display using mRNAs extracted from postnatal day (P)2 and P10 mouse eyes. 4 At P2, ODAG was highly expressed in all the retinal layers (presumptive outer nuclear layer [ONL], presumptive inner nuclear layer [INL], and ganglion cell layer [GCL]), but at P7, its expression decreases, especially in the GCL, and at P14, no apparent expression is detected. To investigate, we generated transgenic mice overexpressing ODAG (ODAG Tg). The mouse Crx promoter, which directs transgene expression in photoreceptors, From th
