Cell adhesion molecules in visual system assembly

视觉系统组装中的细胞粘附分子

• 批准号: 9113573
• 负责人: Jessica E Treisman
• 金额: $ 38.14万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113573
• 关键词: Adherens Junction; Affect; Apical; Apoptosis; Axon; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Death; Cell physiology; Cell surface; Cells; Characteristics; Chickens; Complex; Detection; Development; Disease; Drosophila genus; Embryo; Employee Strikes; Epithelial; Epithelium; Genetic Screening; Goals; Health; Homologous Gene; Homologous Protein; Human; Immunoglobulins; Interneurons; Kidney; Kidney Diseases; Ligands; Location; Mediating; Molecular; Motion; Nervous system structure; Neurons; Pathology; Pattern; Photoreceptors; Pigments; Play; Process; Proteins; Pupil; Retina; Retinal; Retinal Ganglion Cells; Role; Site; Specific qualifier value; Specificity; Structure; Synapses; System; Testing; Tissues; To specify; Up-Regulation; Visual; Visual Motion; Visual system structure; complex biological systems; gain of function; insight; intercalation; loss of function; member; mutant; nephrin; nephrogenesis; neural circuit; postsynaptic; precursor cell; research study; slit diaphragm; vision development; visual information

 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.

 描述（由申请人提供）：细胞表面上的细胞粘附分子促进特定的细胞间相互作用，从而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组织，才能准确地传输视觉信息。 Sidekicks (Sdks) 是免疫球蛋白超家族的成员，与指定脊椎动物视网膜中的突触接触有关。 Sdk-1 也在发育中的肾脏中表达，其上调会导致多种疾病的病理。参与运动检测的光感受器轴突需要果蝇 Sdk 来组织其目标组织（椎板）。 Sdk 还显示出对电路中其他突触层的惊人定位，可检测移动的亮度增量或减量。在瞳孔视网膜等上皮细胞中，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 Roughest (Rst) 和 Hibris (Hbs) 的功能和表达模式重叠，这两种免疫球蛋白超家族蛋白与哺乳动物 NEPH1 和 Nephrin 同源，在肾脏中形成裂隙隔膜。该提案的目标是了解 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电路中哪些细胞表达并需要 Sdk 形成适当的连接。要测试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质相互作用有助于该电路的组装。 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，其中包括多个突触后细胞。第二个目标将利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处发挥作用，以控制细胞重排，从而产生蛹视网膜的高度有序结构。第三个目标将研究 Sdk、Rst 和 Hbs 如何影响彼此的定位和功能，以便了解这些分子如何联合作用以指定视觉系统中的精确细胞接触。此外，将使用遗传筛选来鉴定有助于 Sdk 功能的其他蛋白质。这些研究将深入了解协调细胞间相互作用以组装高度组织化的结构（例如视觉回路和肾缝隔膜）的分子机制。