Mechanism of differential adhesion by protocadherin-cadherin complexes

描述（由申请人提供）：通过协调的细胞运动、区域划分、轴突靶向和突触形成，需要选择性细胞-细胞相互作用来建立脊椎动物神经系统的精确三维结构。钙粘蛋白超家族包括大量不同的细胞表面受体，包括经典钙粘蛋白和原钙粘蛋白。经典的钙粘蛋白和原钙粘蛋白都被认为在发育中的大脑中建立神经回路中发挥作用。虽然经典的钙粘蛋白是已知的嗜同性细胞粘附分子，参与细胞粘附的原钙粘蛋白仍然不确定。在我们以前的工作中，我们发现原钙粘蛋白19（Pcdh 19）与N-钙粘蛋白（Ncad）形成异聚体顺式复合物。在初步的数据，我们表明，Pcdh 19介导的嗜同性粘附的Pcdh 19-Ncad复合物的一部分，虽然它本身不是粘合剂。这个建议的主要假设是，原钙粘蛋白与经典的钙粘蛋白，形成顺式复合物具有独特的粘附性能。为了更详细地研究这一假设，我们提出了以下具体目标。在目的1中，我们将测试的假设，即d-原钙粘蛋白家族的成员形成顺式复合物与经典的钙粘蛋白，并确定这些复合物是否介导嗜同性粘附，因为我们已经表明Pcdh 19-Ncad。在目标2中，我们将首先确定Pcdh 19中构成粘附界面的残基，然后确定这种机制是否适用于Pcdh-Cdh复合物。从这些实验中获得的见解将阐明一种新的细胞粘附机制的分子基础，并将推进我们对原钙粘蛋白和钙粘蛋白功能的认识，为理解这些分子在神经发育中的作用和阐明建立神经连接模式的机制提供必要的基础。 公共卫生相关性：原钙粘蛋白和钙粘蛋白与许多神经发育障碍有关，包括自闭症、精神分裂症、癫痫和精神发育迟滞。尽管原钙粘素对神经发育的重要性，但对其分子和细胞功能或发育作用知之甚少。我们的研究将极大地推进我们对原钙粘蛋白的细胞粘附机制的认识，并为理解它们在脊椎动物神经系统发育中的作用提供基础。

DESCRIPTION (provided by applicant): Selective cell-cell interactions are required to establish the precise three-dimensional architecture of the vertebrate nervous system through coordinated cell movements, regional partitioning, axon targeting and synapse formation. The cadherin superfamily comprises a large, diverse array of cell surface receptors that includes both the classical cadherins and the protocadherins. Both classical cadherins and protocadherins have been proposed to play roles in establishing neural circuitry in the developing brain. While the classical cadherins are known to be homophilic cell adhesion molecules, the involvement of protocadherins in cell adhesion remains uncertain. In our previous work, we showed that Protocadherin-19 (Pcdh19) associates with N-cadherin (Ncad) to form a heteromeric cis-complex. In preliminary data, we show that Pcdh19 mediates homophilic adhesion as part of the Pcdh19-Ncad complex, although it is not adhesive itself. The main hypothesis of this proposal is that protocadherins associate with classical cadherins to form cis-complexes with distinct adhesive properties. To investigate this hypothesis in more detail we propose the following Specific Aims. In Aim 1, we will test the hypothesis that members of the d-protocadherin family form cis-complexes with classical cadherins and determine whether these complexes mediate homophilic adhesion, as we have shown for Pcdh19-Ncad. In Aim 2, we will first determine the residues in Pcdh19 that constitute the adhesive interface, and then determine if this mechanism is general to Pcdh-Cdh complexes. Insights gained from these experiments will elucidate the molecular underpinnings of a novel mechanism of cell adhesion and will advance our knowledge of protocadherin and cadherin function, providing an essential foundation for understanding the roles of these molecules in neural development and elucidating the mechanisms that establish patterns of neural connectivity. PUBLIC HEALTH RELEVANCE: Protocadherins and cadherins have been implicated in a number of neurodevelopment disorders, including autism, schizophrenia, epilepsy and mental retardation. Despite the importance of protocadherins to neural development, very little is known about their molecular and cellular functions or developmental roles. Our studies will dramatically advance our knowledge of the mechanism of cell adhesion by the protocadherins and provide a foundation for understanding their roles in the development of the vertebrate nervous system.