ARF Controls Vascular Regression During Eye Development

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DESCRIPTION (provided by applicant): The major goal of this proposal is to understand molecular events preventing primary vitreous hyperplasia and guiding the regression of the hyaloid vascular system (HVS) during eye development. I will specifically investigate the roles of Arf, an important mammalian tumor suppressor gene, and Platelet-derived growth factor receptor 2 (Pdgfr2), which contributes to a variety of developmental, physiological, and pathological processes. To assure normal development, mammalian cells have mechanisms to check cell proliferation stimuli and preserve cell cycle arrest. When gone awry, excess mitogenic signals lead to developmental defects and a wide variety of pathological processes. The Arf gene product, p19Arf, was initially discovered to play a key role as a "fuse" to control excess mitogens and prevent tumor formation. Work supported by the first cycle of this R01 has challenged this simple paradigm as I have shown p19Arf plays an essential function during mouse eye development. Without it, excess numbers of perivascular cells envelop the hyaloid vasculature in the vitreous, preventing their normal involution during the later stages of eye development. Mice lacking Arf are blind due to a pathological process strikingly similar to severe persistent hyperplastic primary vitreous (PHPV). We have identified a new biochemical and genetic pathway in which the Arf gene product blocks signals stemming from Pdgfr2 to prevent primary vitreous hyperplasia, likely by repressing the expression of the receptor. In the current proposal, I will tackle the critical questions that still cloud our understanding of the functional relationship between the two gene products. I will take advantage of existing cell culture system and mouse models one of which will be developed in this proposal to (1) identify how p19Arf- dependent control of Pdgfr2 influences eye development; (2) uncover mechanisms by with Pdgfr2 fosters vitreous hyperplasia without Arf; and (3) elucidate mechanisms by which Arf represses Pdgfr2 expression. Insight into how Pdgfr2 contributes to the eye pathology in the absence of Arf and how p19Arf controls Pdgfr2-dependent signals will address fundamental aspects of eye development; leave me ideally positioned to address whether genetic abnormalities in this new "pathway" contribute to the pathogenesis of PHPV or other vitreoretinopathies; and begin to investigate whether pharmacological disruption of Pdgfr2 signaling can ameliorate the disease. PUBLIC HEALTH RELEVANCE: The major goal of this proposal is to understand molecular events preventing primary vitreous hyperplasia and guiding the regression of the hyaloid vascular system (HVS) during eye development. I have identified a new biochemical and genetic pathway in which the Arf gene product, p19Arf, blocks signals stemming from Platelet-derived growth factor receptor 2 (Pdgfr2) to prevent primary vitreous hyperplasia, likely by repressing the expression of the receptor. I will use cell culture-based and mouse models to uncover how Pdgfr2 contributes to the eye pathology in the absence of Arf and how p19Arf controls Pdgfr2-dependent signals.