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稳态至关重要，并且间隙连接促进相邻纤维细胞之间小分子的扩散。然而，最近我们有证据表明，像蛋白质这样的大分子也可以在纤维细胞之间扩散。细胞间蛋白扩散的通道可能是有限的细胞-细胞融合区域。晶状体核心细胞间融合的存在保证了晶状体中央区域作为合胞体的功能。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体膜蛋白。它是克劳丁超家族的一员，在晶状体中具有粘附功能。在初步实验中，通过插入诱变，Lim2基因座在小鼠中被破坏，导致Lim2功能缺失。值得注意的是，在缺乏Lim2的情况下，晶状体合胞体没有形成。此外，对Lim2-null小鼠透镜的激光分析表明，透镜的内部折射特性受到了严重的干扰。这些观察结果表明晶状体膜蛋白（Lim2）的表达、合胞组织和晶状体的折射功能之间存在联系。目前的应用将研究大分子在晶状体细胞间扩散的分子机制，Lim2在晶状体合胞体形成中的作用，以及合胞体组织与晶状体梯度折射率（GRIN）之间的关系。这些研究有望为先前未被怀疑的大分子细胞间扩散与透镜光学质量之间的联系提供新的见解。这些信息反过来又会告诉我们眼睛中的图像形成和晶状体在光学序列中的作用。公共卫生相关性：晶状体的作用是将光线聚焦在视网膜上。这个应用程序将研究蛋白质在晶状体内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.