Cadherin mediated interactions in the hippocampus

钙粘附素是一种依赖钙离子的细胞黏附，在胚胎细胞的分化和功能分离中起着关键作用。它们通过亲和性结合机制连接表达相同钙粘附素类型的细胞，并需要在膜的两侧进行相互作用才能发挥这一功能。在神经系统中，钙粘附素由不同的轴突群表达，并与调节神经元的特异性有关。钙粘附素分子最近被定位于突触连接，并被认为在突触的规范和可塑性中发挥作用。本项目将研究T-钙粘蛋白在海马体结构中的功能和运作机制，它通过糖基磷脂基锚被锚定在膜上。T-钙粘蛋白分散地定位于海马层，轴突和树突相互作用形成突触接触。这表明T-钙粘附素在轴突引导和靶点选择和/或突触的轴突相互作用中发挥着独特的作用。利用缺乏T-钙粘蛋白基因功能的小鼠，本项目将研究T-钙粘附素在建立海马区回路中的作用。首先，我们将确定T-钙粘附素是否是突触连接的一个组成部分，以及它的表达如何与在突触中表达的经典钙粘附素在T-钙粘附素表达区域的关系。其次，我们将探讨T-钙粘蛋白在T-钙粘素缺失突变小鼠透明层寻路和突触形成过程中苔藓纤维轴突的轴突相互作用。第三，我们将在体外模型中剖析T-钙粘附素在神经元分化和突触形成中的作用。最后，我们将通过鉴定与T-钙粘蛋白相关的蛋白质来分析T-钙粘蛋白的作用机制。这项工作将有助于分子理解认知功能中涉及的有趣神经回路形成的潜在机制。

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.