Recognition coding at CNS synapses

描述（由申请人提供）：皮层突触发生最初被认为是不精确的，并随着时间的推移而完善。我们怀疑中枢神经系统突触的最终排列是基于特定的突触前-突触后相互作用的“排序”或“重组”的一个例子。通过它们的结合特异性，粘附分子是在胚胎发育过程中将细胞“分类”成组和层的基础，并且被认为在突触发生过程中也具有类似的功能。在突触发生过程中，介导精细特异性和分选的分子预计会在相同类型和相同谱系的神经元中以不可预测的组合差异表达。簇状原钙粘蛋白（Pcdhs）是一种新型的神经粘附/识别分子，具有调节突触识别的分子特性。它们的基因被组织成不同寻常的簇，这可能反映了不同Pcdhs的不可预测组合可以在相似的神经元类型中表达的机制。根据我们的数据和其他人的工作，我们假设Pcdhs是神经元之间识别“代码”的基础，通过控制胞内膜结合突触蛋白的分类，在突触发生过程中正确匹配新生突触，从而导致突触成熟。我们提出两个具体目标来检验我们的假设。在Aim 1中，我们将确定Pcdhs是否实际上是粘附/识别分子，并表征它们的细胞质相互作用。在目标2中，我们将描述Pcdh的亚细胞运输和突触插入过程，我们怀疑这是Pcdh介导的正确匹配突触成熟的基础。在完成这些目标后，我们期望对细胞间相互作用在突触发生中的作用有更好的理解。

DESCRIPTION (provided by applicant): Cortical synaptogenesis is thought to be initially imprecise and refined over time. We suspect that the final arrangement of CNS synapses is an example of "sorting" or "reshuffling" based on specific pre-to- postsynaptic interactions. Via their binding specificity, adhesion molecules are the basis for "sorting" cells into groups and layers throughout embryonic development and have been thought to function similarly during synaptogenesis as well. Molecules that mediate fine specificity and sorting during synaptogenesis are expected to be differentially expressed in unpredictable combinations in neurons of the same type and from the same lineages. The clustered protocadherins (Pcdhs), novel putative neural adhesion/recognition molecules, exhibit properties expected of molecules that mediate a precise level of synaptic recognition. Their genes are organized into unusual clusters that may reflect the mechanism by which unpredictable combinations of different Pcdhs can be expressed within similar neuronal types. Based on our data and work from others, we hypothesize that the Pcdhs are a basis for a recognition "code" among neurons by controlling the sorting of intracellular membrane bound synaptic proteins to correctly matched nascent synapses during synaptogenesis resulting in synaptic maturation. We propose two Specific Aims to test our hypothesis. In Aim 1, we will determine whether Pcdhs are actually adhesion/recognition molecules and characterize their cytoplasmic interactions. In Aim 2, we will characterize the subcellular trafficking and synaptic insertion processes of the Pcdhs that we suspect underlie Pcdh mediated maturation of correctly matched synapses. Upon completion of these Aims we expect to have a better understanding of the role of cell-cell interactions in synaptogenesis.