Determinants of Lens Fiber Cell Structure

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT The primary function of the lens is to focus light on the retina so as to allow us to see. This function relies on the transparency of the lens, and this transparency depends on the precise organization of its primary constituent cell type, the lens fiber cells. Our goal is to understand what determines the correct cellular organization within the lens that confers its transparency. As lens fiber cells differentiate, they elongate and make direct interactions between themselves to create a highly ordered, tissue-wide cellular organization that confers the overall architecture of the tissue and its transparency. Any disruption of this organization leads to opaque lenses (i.e. cataracts) that are the most common cause of blindness world-wide. We recently discovered two proteins that dictate lens architecture: they are Dlg-1 and Scrib1. Furthermore, we determined that Dlg-1 is critical for conferring planar cell polarity (PCP) in mice. PCP refers to the coordination of cells such that they move, orient, and/or proliferate in a particular direction critical for the normal morphogenesis of the relevant tissue. Another core PCP protein, Vangl2, has been implicated in determining lens shape. Here we provide evidence that Scrib as well as the newly identified PCP protein, Dlg-1, and the well-established PCP protein, Vangl2 determine overall lens architecture. They do so by determining the overall shape of lens fiber cells, and the cell:cell contacts between lens fiber cells within the equatorial region of the lens. Unclear is whether this is due to PCP-dependent or PCP-independent effects of these proteins on lens architecture. The primary goal of this exploratory R21 grant application is to distinguish between these two possibilities. We will approach this using genetic approaches that have been well-validated in other invertebrates as well as more detailed mechanistic studies including the use of state-of-the-art high resolution STED microscopy to resolve the interactions between core PCP proteins and other factors involved in determining lens shape. The two aims of this R21 proposal are to 1) Determine whether planar cell polarity is key to determining lens architecture and 2) Define the interplay between planar cell polarity factors and cell:cell adhesion factors in determining lens architecture. Completion of these studies will provide important and novel insights into the mechanisms required to achieve and maintain lens transparency, a research priority of the NEI, and have an impact on the overarching NEI goal of better preventing and treating cataracts.