LIM2 AND THE LENS CORE SYNCYTIUM

描述(申请人提供)：纤维细胞之间的细胞间通讯对晶状体内稳态至关重要，众所周知，缝隙连接促进了小分子在相邻纤维细胞之间的扩散。然而，最近我们获得的证据表明，蛋白质等大分子也可以在纤维细胞之间扩散。细胞间蛋白质扩散的管道可能是有限的细胞-细胞融合区域。晶状体核心细胞之间的融合确保了晶状体中央区域作为合胞体发挥作用。核心合胞体的生理意义尚不清楚。LIM2是晶状体中含量第二丰富的整膜蛋白。它是Claudin超家族的成员，在晶状体中具有假定的粘连功能。在初步实验中，小鼠的Lim2基因座被插入突变破坏，导致Lim2的功能缺失。值得注意的是，在没有LIM2的情况下，晶状体合胞体没有形成。此外，对LIM2缺失的小鼠晶状体的激光分析显示，晶状体的内部折射特性受到了严重干扰。这些观察表明晶状体膜蛋白(LIM2)的表达、合胞组织和晶状体中的屈光功能之间存在联系。目前的应用将研究大分子在晶状体细胞之间扩散的分子机制，LIM2在晶状体合体形成中的作用，以及合胞结构与晶状体梯度折射率(GRIN)的关系。这些研究有望为大分子的细胞间扩散和晶状体光学质量之间以前未被怀疑的联系提供新的见解。这些信息将反过来告诉我们眼睛中图像形成的观点，以及晶状体在光学系统中的作用。与公共健康相关：晶状体的作用是将光线急剧聚焦在视网膜上。这项应用将研究晶状体内蛋白质的细胞间运动如何影响其光学质量。

DESCRIPTION (provided by applicant): Intercellular communication between fiber cells is critical for lens homeostasis and it is well established that gap junctions facilitate the diffusion of small molecules between adjacent fiber cells. Recently, however, we have obtained evidence that large molecules such as proteins can also diffuse between fiber cells. The conduits for intercellular protein diffusion may be regions of limited cell-cell fusion. The presence of fusions between cells in the lens core ensures that the central region of the lens functions as a syncytium. The physiological significance of the core syncytium is not known. Lim2 is the second most abundant integral membrane protein in the lens. It is a member of the claudin super- family and has putative adhesive functions in the lens. In preliminary experiments, the Lim2 locus was disrupted in mice by insertional mutagenesis, resulting in a functional null for Lim2. Significantly, in the absence of Lim2, the lens syncytium did not form. Furthermore, laser analysis of Lim2-null mouse lenses revealed that the internal refractive properties of the lens were profoundly disturbed. These observations suggest a link between the expression of a lens membrane protein (Lim2), syncytial organization, and refractive function in the lens. The current application will examine the molecular mechanism by which macromolecules diffuse between lens cells, the role of Lim2 in the formation of the lens syncytium, and the relationship between syncytial organization and the lens gradient refractive index (GRIN). These studies are expected to provide novel insights into the previously unsuspected link between intercellular diffusion of macromolecules and lens optical quality. This information will, in turn, inform our view of image formation in the eye and the role of the lens in the optical train. PUBLIC HEALTH RELEVANCE: The role of the lens is to focus light sharply on the retina. This application will examine how the intercellular movement of protein within the lens contributes to its optical quality.