NCAM influences RGC numbers: mechanisms and implications for vision

我们的实验室一直对探索与中枢神经系统（CNS）神经元存活相关的机制感兴趣。我们最近的研究，通过NSERC的资助，已经证明了神经细胞粘附分子（NCAM）及其聚唾液酸化形式（PSA-NCAM）在视网膜中年轻成年CNS神经元的存活中发挥作用。NCAM是一种细胞表面蛋白，PSA是一种几乎完全位于NCAM上的碳水化合物;两者都涉及细胞发育和再生的各种功能。 越来越多的证据表明，NCAM在成人神经系统中起着重要作用;然而，其对神经元存活和衰老功能的影响尚未被描述。 啮齿类动物的视觉系统提供了一个通用的模型，用于研究视网膜神经节细胞（RGC）的生存，这是视网膜内的CNS神经元，以及用于评估药物治疗和其他潜在治疗的有效性。我们现在有初步的数据表明，NCAM在影响CNS神经元存活的动物年龄的重要作用：RGC密度显着较高的年轻成年和老年NCAM -/-小鼠。尽管有较高数量的RGC，我们有初步的数据，这些动物的视觉能力表明，神经元功能可能不正常。 这些发现构成了我们计划更完整地定义NCAM/PSA-NCAM在成年和衰老动物神经元存活中的作用以及研究其分子机制的基础工作。 该项目的总体目标是评估NCAM和PSA-NCAM在介导老化CNS中RGC存活中的作用。 具体而言，我们提出了以下问题：（1）在老化过程中，NCAM和PSA-NCAM的存在或缺失是否会改变视网膜中CNS神经元的存活;（2）NCAM和PSA-NCAM的缺失是否会对视觉系统产生功能性影响;（3）NCAM和PSA-NCAM介导RGC存活的机制是什么？ 旨在回答这些问题的研究很重要，因为它与从根本上理解为什么神经元会随着年龄的增长而死亡有关。

Our laboratory has been interested in exploring mechanisms that are relevant to the survival of central nervous system (CNS) neurons. Our recent studies, made possible by NSERC funding, have demonstrated that the neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) play roles in survival of young adult CNS neurons in the retina. NCAM is a cell surface protein and PSA is a carbohydrate localized almost exclusively on NCAM; both have been implicated in various functions of cellular development and regeneration. There is increasing evidence suggesting that NCAM plays an essential role in the adult nervous system; however, its influence on neuron survival and function in aging has not yet been described. The rodent visual system provides a versatile model for studying the survival of retinal ganglion cells (RGCs), which are CNS neurons within the retina, as well as for evaluating the effectiveness of pharmacotherapies and other potential treatments. We now have preliminary data indicating that NCAM plays an important role in influencing CNS neuron survival as the animal ages: RGC densities are significantly higher in young adult and older NCAM -/- mice. Despite having higher numbers of RGCs, we have preliminary data concerning visual abilities in these animals indicating that neuronal function may not be normal. These findings constitute the foundational work upon which we plan to more completely define the role as well as investigate molecular mechanisms of NCAM/PSA-NCAM in neuron survival in adult and aging animals. The overall aim of this project is to evaluate the role of NCAM and PSA-NCAM in mediating the survival of RGCs in the aging CNS. Specifically, we are asking the following questions: (1) is the survival of CNS neurons in the retina altered during aging by the presence or absence of NCAM and PSA-NCAM; (2) does the absence of NCAM and PSA-NCAM have functional consequences for the visual system; and (3) what are the mechanisms by which NCAM and PSA-NCAM mediate RGC survival? Research designed to answer these questions is important as it is relevant to fundamentally understanding why neurons die as they age.