Cell adhesion molecules in visual system assembly

 描述（由申请人提供）：细胞表面上的细胞粘附分子促进特异性细胞-细胞相互作用，指导复杂结构的组装。在视觉系统中，视网膜本身和视觉电路都必须精确地组织，以准确地传递视觉信息。Sdks是免疫球蛋白超家族的成员，其参与了脊椎动物视网膜中突触接触的指定。Sdk-1也在发育中的肾脏中表达，其上调有助于几种疾病状况的病理学。果蝇Sdk是参与运动检测的光感受器轴突所必需的，以组织它们的靶组织，板层。Sdk还显示了在检测移动亮度增量或减量的电路中的其他突触层的显著定位。在上皮细胞如瞳孔视网膜中，Sdk特异性地定位于三个或更多个细胞之间的接触。Sdk的功能和表达模式与Roughest（Rst）和Hibris（Hbs）的功能和表达模式重叠，Roughest和Hibris是与哺乳动物NEPH 1和Nephrin同源的另外两种免疫球蛋白超家族蛋白，其形成肾脏中的狭缝隔膜。本提案的目标是了解Sdk如何与这些粘附分子相互作用，以介导组织视觉系统组装的特定细胞接触。第一个目标是评估视觉回路中的哪些细胞表达并需要Sdk来形成适当的连接。待检验的假设是，在运动检测回路中的神经元上表达的Sdk通过定义突触层的亲同性相互作用而有助于该回路的组装。Sdk定位于三细胞接触表明，它也可能是视觉系统四分体突触特征形成的基础，视觉系统包括多个突触后细胞。第二个目标将使用功能丧失和功能获得实验来确定Sdk如何在上皮三细胞接触中起作用以控制产生蛹视网膜的高度有序结构的细胞重排。第三个目标将研究Sdk，Rst和Hbs如何影响彼此的定位和功能，以了解这些分子如何组合作用，以指定视觉系统中精确的细胞接触。此外，其他有助于Sdk功能的蛋白质将通过遗传筛选来鉴定。这些研究将提供深入了解的分子机制，协调细胞间的相互作用，以组装高度组织化的结构，如视觉电路和肾裂隔膜。

 DESCRIPTION (provided by applicant): Cell adhesion molecules on the cell surface promote specific cell-cell interactions that direct the assembly of complex structures. In the visual system, both the retina itself and the visual circuitry must be precisely organized in order to accurately transmit visual information. Sidekicks (Sdks) are members of the immunoglobulin superfamily of proteins that have been implicated in specifying synaptic contacts in the vertebrate retina. Sdk-1 is also expressed in the developing kidney, where its upregulation contributes to the pathology of several disease conditions. Drosophila Sdk is required for photoreceptor axons involved in motion detection to organize their target tissue, the lamina. Sdk also shows a striking localization to other synaptic layers in the circuits that detect moving brightness increments or decrements. In epithelia such as the pupil retina, Sdk is specifically localized to contacts between three or more cells. The functions and expression patterns of Sdk overlap with those of Roughest (Rst) and Hibris (Hbs), two other immunoglobulin superfamily proteins homologous to mammalian NEPH1 and Nephrin, which form the slit diaphragm in the kidney. The goal of this proposal is to understand how Sdk interacts with these adhesion molecules to mediate specific cell contacts that organize visual system assembly. The first aim will assess which cells in the visual circuitry express and require Sdk to form appropriate connections. The hypothesis to be tested is that Sdk expressed on neurons in the motion detection circuit contributes to the assembly of this circuit through homophilic interactions that define synaptic layers. The localization of Sdk to tricellular contacts suggests that it may also underlie the formation of the tetrad synapses characteristic of the visual system, which includes multiple postsynaptic cells. The second aim will use loss of function and gain of function experiments to determine how Sdk acts at epithelial tricellular contacts to control the cell rearrangements that produce the highly ordered structure of the pupal retina. The third aim will investigate how Sdk, Rst and Hbs influence each other's localization and function, in order to understand how these molecules act in combination to specify precise cellular contacts in the visual system. In addition, other proteins that contribute to Sdk function will be identified usinga genetic screen. These studies will provide insight into the molecular mechanisms that coordinate cell-cell interactions to assemble highly organized structures such as the visual circuitry and the kidney slit diaphragm.