Cadherin mediated interactions in the hippocampus

钙粘蛋白是一种钙依赖性的细胞粘附物质，在胚胎细胞分化成功能不同的细胞群中起着关键作用。它们通过亲同源结合机制连接表达相同钙粘蛋白类型的细胞，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，钙粘蛋白通过不同的轴突群表达，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，并被认为在突触规范和可塑性中发挥作用。本项目将研究通过糖基磷脂酰锚定在海马体膜上的t -钙粘蛋白的功能和作用机制。t -钙粘蛋白在轴突和树突相互作用形成突触接触的海马体椎板中分散分布。这表明t -钙粘蛋白在轴突引导和靶标选择和/或突触的轴突相互作用中起着独特的作用。本项目将利用T-cadherin基因功能缺失小鼠，研究T-cadherin在海马回路建立中的功能。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T-钙粘蛋白表达区域突触中表达的经典钙粘蛋白的表达相关。其次，我们将研究T-钙粘蛋白在苔藓纤维轴突的轴突相互作用中的作用，在T-钙粘蛋白缺陷小鼠突变体的寻路和透明层突触形成过程中。第三，我们将在体外模型中解剖t -钙粘蛋白在神经元分化和突触形成中的作用。最后，我们将通过表征与T-cadherin相关的蛋白来开始分析T-cadherin的功能机制。这项工作将有助于对认知功能中有趣的神经回路形成机制的分子理解。

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.