Mechanisms of p19Arf-Mediated Regulation of Perivascular Cell Biology During Mammalian Eye Development
Iqbal, Nida S.
MetadataShow full item record
Since its discovery in 1995, p19Arf has been under critical interrogation for its role as a potent cell cycle regulator and tumor suppressor. In the last decade, there has been considerable evidence describing an essential function for p19Arf during mammalian eye development. In this context, p19Arf is required for the ultimate involution of the hyaloid vasculature system that exists in the primary vitreous space and serves to nourish the lens and retina. Knock-out mouse models for p19Arf demonstrate that in the absence of Arf, there is an abnormal accumulation of cells that persist into the adult secondary vitreous and cause detrimental ocular defects including blindness, retinal detachment and lens opacity. It has been further demonstrated that p19Arf enacts a dual mechanism to inhibit the accumulation of the perivascular cells that occupy the vitreous space during development and lead to the clearing of these cells followed by eventual involution of the underlying vasculature system. Platelet-derived growth factor receptor β (Pdgfrβ) is required for the accumulation of cells in the absence of Arf and while it is clear that p19Arf utilizes a p53-dependent mechanism to inhibit Pdgfrβ transcription, the mechanism by which it can inhibit Pdgfrβ protein in the absence of p53 is not well defined. Further, the biological consequences of Arf expression have, to date, only been studied in a context in which Arf is not normally expressed, such as during tumor progression and culture shock. This work addresses these two open questions. First, I will discuss a novel capacity for p19Arf to employ microRNAs outside of the p53 pathway to lead to repression of Pdgfrβ protein. Next I will describe an ex vivo cell culture system to study unexplored facets of Arf biology in a context in which it is endogenously expressed.