Cell adhesion molecules in visual system assembly

 描述(申请人提供)：细胞表面的细胞黏附分子促进特定的细胞与细胞之间的相互作用，指导复杂结构的组装。在视觉系统中，为了准确地传递视觉信息，视网膜本身和视觉回路都必须被精确地组织起来。Sidekicks(SDK)是免疫球蛋白超家族的成员，与脊椎动物视网膜中特定的突触接触有关。SDK-1在发育中的肾脏中也有表达，它的上调导致了几种疾病的病理变化。参与运动检测的光感受器轴突需要果蝇SDK来组织它们的目标组织--板层。SDK还显示了检测运动亮度增加或减少的电路中其他突触层的惊人定位。在像瞳孔视网膜这样的上皮细胞中，SDK专门定位于三个或更多细胞之间的接触。SDK的功能和表达模式与另外两个免疫球蛋白超家族蛋白Rroughest(RST)和Hibris(HBS)重叠，这两个蛋白与哺乳动物的NEPH1和NePhrin同源，形成了肾脏的裂隙横隔膜。这项提议的目标是了解SDK如何与这些黏附分子相互作用，以调节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形成适当的连接。需要检验的假设是，运动检测电路中神经元上表达的SDK通过定义突触层的同嗜性相互作用促进了这一电路的组装。SDK与三细胞接触的定位表明，它也可能是视觉系统特有的四分体突触形成的基础，其中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如何作用于上皮三细胞接触，以控制细胞重排，从而产生高度有序的幼虫视网膜结构。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结合在一起，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基因筛查来识别。这些研究将提供对协调细胞-细胞相互作用以组装高度组织的结构(如视觉回路和肾裂隙横隔膜)的分子机制的洞察。

 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.