Role of Cited2 in lens development and hyaloid vascular regression

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DESCRIPTION (provided by applicant): Cited2 (CBP/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2) is a founding member of a new family of transcriptional modulators. My laboratory cloned Cited2 and showed that Cited2 is induced by many biological stimuli including cytokines, serum and LPS. It is widely expressed and is a transforming gene when overexpressed. In order to address the role of Cited2 in vivo, we generated mice with a null mutation at the Cited2 locus and found that deletion of Cited2 causes Cited2-/- embryos to die at mid- to late gestation with several developmental defects. Cited2 expression is detectable in the developing lens. Histological examination of Cited2-/- embryos revealed persistent lens stalk, a smaller lens and hyaloid hypercellularity consisting of aberrant vasculature in the eye. The latter is similar to the pathological features of PHPV (Persistent hyperplastic primary vitreous), a congenital eye disorder leading to abnormal lenticular development and secondary changes of the retina and the eye. Tissue specific deletion of Cited2 in the lens also resulted in lens stalk formation, a smaller lens and failed regression of hyaloid vascular system (HVS) in adult eyes. These results suggest that they are primary defects associated with loss of Cited2 expression in the lens and that Cited2 is involved in lens morphogenesis and hyaloid vascular formation/regression during development. Cited2 is a negative modulator for HIF-1 function and loss of Cited2 may result in upregulated HIF-1 mediated hypoxic responses. This mechanism is partially responsible for the heart defects observed in Cited2 null embryos. Lens-specific deletion of HIF-1 eliminates the aberrant hyaloid hypercellularity in Cited2 deficient embryos, suggesting that dysregulated HIF-1 signaling may play a role in aberrant HVS formation in Cited2-/- eyes. Although it is known that lens is a hypoxic organ and HIF-1 is highly expressed in the lens epithelial cells, a direct and detailed examination of the hypoxia level of a developing mouse lens and the consequences of its deregulation has never been performed. This pilot study, which is a new research area for the principal investigator, attempts generate compound mice with deletions of Cited2 and HIF-1 or VEGF to explore the hypothesis that a Cited2-HIF-1 genetic interaction is essential for HVS formation and regression. Since lens- specific Cited2 knockout mouse exhibits failed HVS regression and deletion of HIF-1 rescues the abnormal hyaloid vasculature in Cited2 knockout eyes, lens-specific Cited2 knockout mice could not only be used as a novel disease model for PHPV but also for testing potential HIF-1 inhibitors. PUBLIC HEALTH RELEVANCE: The accomplishment of the proposed study will not only advance our knowledge in the lens development and the influence of hypoxia on the formation and regression of hyaloid vascular system but also provide potential therapeutic principles in treating eye disorders and other systemic diseases with dysregulated HIF-1 signaling.