Cell-Cell Signaling in Visual Development

描述(申请人提供)：视觉系统的正确运作需要从眼睛到大脑的轴突连接以精确定义的空间顺序发展。我们研究的长期目标是识别细胞间的信号分子，并描述它们在指导视神经轴突连接的精确发展中的功能和作用机制。该提案将重点放在视网膜神经节细胞轴突及其向顶盖的投射，顶盖是长期以来一直是主要模型系统的视网膜轴突靶标。目的1提出研究视网膜顶盖系统中新的分子相互作用。淀粉样前体蛋白(APP)是一种细胞表面分子，在阿尔茨海默病的病理过程中具有重要作用，但其正常功能尚不清楚。长期以来，APP一直被认为是细胞表面的配体或受体。在初步研究中，APP的结合伙伴已被确定，并在视网膜顶盖系统中显著表达。将继续研究这些蛋白质的分子相互作用，以及它们对APP信号和视网膜轴突生长发育的影响。目的二是研究顶盖梯度的形成机制。众所周知，肾上腺素作为顶盖轴突映射的分级位置标记。然而，最初建立这些梯度的机制并没有被很好地理解。将继续进行研究，以确定上游分子体系中最初将非分级分布转变为分级分布的步骤，并确定顶盖中梯度形成的生化机制。目标3是描述视网膜轴突中基于RNA的调节机制。越来越多的证据表明，受调控的蛋白质合成发生在轴突内，并可能具有重要的功能。这开辟了一个令人振奋的新研究领域，但机制仍未得到很好的描述。基于RNA的调节机制将在视网膜神经节细胞轴突中进行研究，包括合成的位置和动力学，以及对细胞外提示做出反应的mRNAs调节翻译的机制。虽然我们的主要目标是阐明基本的分子机制，但这项工作对疾病有更广泛的影响。APP在阿尔茨海默病中的作用很重要，包括视网膜的病理。识别调节APP加工的配体可能会导致抑制β淀粉样蛋白产生的治疗靶点。更广泛地说，识别和表征视觉系统中新的细胞-细胞信号线索的研究可能会导致用于维持、修复或再生视觉连接的治疗剂。

DESCRIPTION (provided by applicant): Correct functioning of the visual system requires axonal connections from eye to brain to develop with precisely-defined spatial order. The broad long-term objective of our studies is to identify cell-cell signaling molecules, and characterize their functions and mechanisms of action in guiding the precise development of visual axonal connections. The proposal focuses on retinal ganglion cell axons, and their projections to the tectum, a retinal axon target which has long been a major model system. Aim 1 proposes to study novel molecular interactions in the retinotectal system. The Amyloid Precursor Protein (APP) is a cell surface molecule with important roles in Alzheimer's pathology, but its normal functions are not well understood. APP has long been proposed to act as a cell surface ligand or receptor. In preliminary studies, binding partners for APP have been identified and are prominently expressed in the retinotectal system. Studies will be continued into the molecular interactions of these proteins, and their effects on APP signaling and retinal axon growth and development. Aim 2 is to study mechanisms of tectal gradient formation. Ephrins are known to act as graded positional labels for axon mapping in the tectum. However, the mechanisms that initially set up these gradients are not well understood. Studies will be continued to identify the steps in the upstream molecular hierarchy that initially convert a non-graded to a graded distribution, and to identify biochemical mechanisms for gradient formation in the tectum. Aim 3 is to characterize RNA-based mechanisms for regulation in retinal axons. Evidence has accumulated to show that regulated protein synthesis occurs within axons and can have important functions. This has opened up an exciting new field of study, but the mechanisms remain poorly characterized. RNA-based regulation mechanisms will be studied in retinal ganglion cell axons, including the location and dynamics of synthesis, and mechanisms for regulated translation of mRNAs in response to extracellular cues. While our primary goal is to elucidate basic molecular mechanisms, the work has broader implications for disease. APP is important for its roles in Alzheimer's disease, including pathology of the retina. Identification of ligands that regulate APP processing may lead to therapeutic targets to inhibit production of beta amyloid. More generally, studies to identify and characterize novel cell-cell signaling cues in the visual system, may lead to therapeutic agents for maintenance, repair or regeneration of visual connections.