Cadherin mediated interactions in the hippocampus

钙粘蛋白介导的海马相互作用

• 批准号: 6583736
• 负责人: BARBARA RANSCHT
• 金额: $ 20.05万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583736
• 关键词: axon; biological signal transduction; brain mapping; cadherins; cell cell interaction; developmental neurobiology; embryo /fetus tissue /cell culture; hippocampus; laboratory mouse; membrane proteins; mossy fiber; neuronal guidance; protein localization; protein protein interaction; protein structure function; synapses; synaptogenesis; transfection

Cadherins are calcium-dependent cell adhesion that play pivotal roles in the specification of embryonic cells and their segregation into functionally distinct groups. They operate by connecting cells expressing the same cadherin type through a homophilic binding mechanism, and require interactions on both sides of the membrane for this function. In the nervous system, cadherins are expressed by e distinct axon populations, and are implicated to regulate neuronal specificity. Cadherin molecules have recently been localized in synaptic junctions, and are suggested to play a role in synapse specification and plasticity. This project will investigate in the hippocampal formation the function and mechanism of operation of T-cadherin that is anchored to the membrane through a glycosylphosphatidyl anchor. T-cadherin is discretely localized in hippocampal laminae where axons and dendrites interact to form synaptic contacts. This suggests that T-cadherin plays a distinct role in axonal interactional interactions either during axon guidance and target selection, and/or at synapses. Using mice deficient for T-cadherin gene function, this project will investigate the function of T-cadherin in the establishment of hippocampal circuitry. First, we will determine if T- cadherin is a component of synaptic junctions, and how its expression relates to that of the classical cadherins that are expressed in synapses in areas of T-cadherin expression. Second, we will address the role of T- cadherin in axonal interactions of mossy fiber axons during pathfinding and synapse formation in the stratum lucidum in T-cadherin-deficient mouse mutants. Third, we will dissect T-cadherin's role in neuronal differentiation and synapse formation in an in vitro model. Lastly, we will begin to analyze the mechanism of T-cadherin's function by characterizing proteins associated with T-cadherin. This work will contribute to the molecular understanding of the mechanisms underlying the formation of the intriguing neuronal circuitry involved in cognitive functions.

钙粘蛋白是一种钙依赖性的细胞粘附蛋白，在胚胎细胞的特化和分化中起着关键作用。它们通过连接表达相同钙粘蛋白类型的细胞通过嗜同性结合机制来运作，并且需要膜两侧的相互作用来实现这一功能。在神经系统中，钙粘蛋白由不同的轴突群表达，并参与调节神经元特异性。钙粘蛋白分子最近被定位于突触连接，并建议发挥作用，突触规范和可塑性。本计画将探讨在海马结构中，借由糖基磷脂锚而锚定在细胞膜上的T-钙黏着蛋白的功能与运作机制。T-钙粘蛋白离散地定位于海马板层中，轴突和树突相互作用以形成突触接触。这表明T-钙粘蛋白在轴突引导和靶选择期间和/或在突触处的轴突间相互作用中起着独特的作用。本研究以T-cadherin基因功能缺陷的小鼠为研究对象，探讨T-cadherin在海马神经回路建立中的作用。首先，我们将确定T-钙粘蛋白是否是突触连接的一个组成部分，以及它的表达如何与在T-钙粘蛋白表达区域的突触中表达的经典钙粘蛋白的表达相关。第二，我们将解决的作用，T-钙粘蛋白在苔藓纤维轴突轴突的轴突相互作用，在T-钙粘蛋白缺乏突变体小鼠的透明层中的寻路和突触形成。第三，我们将在体外模型中剖析T-钙粘蛋白在神经元分化和突触形成中的作用。最后，我们将开始通过鉴定与T-钙粘蛋白相关的蛋白质来分析T-钙粘蛋白的功能机制。这项工作将有助于从分子水平上了解参与认知功能的有趣神经元回路形成的机制。