Protocadherin signaling in the central nervous system

大脑的正常功能依赖于精确的神经元连接模式，而异常的神经元连接模式则依赖于神经元之间的连接模式。 连通性导致人类神经和精神疾病。人类的大脑由 大约有1000亿个神经元和数万亿个突触。由于巨大的神经元多样性， 惊人的突触复杂性，很少有人知道的分子机制，导致 不同神经元类型中特定突触的组装。原钙粘蛋白（Pcdh）基因（14 Pcdh-a，22 Pcdh-fi 和小鼠中的22 Pcdh-y）是这种作用的有吸引力的候选者，因为它们可以潜在地产生 通过细胞特异性启动子激活和顺式- 选择性剪接已经表明，不同的组合Pcdh表达模式可能 指定神经元类型及其连接。为了评估它们在神经发育中的作用，我们启动了 使用转基因小鼠对这些基因进行功能分析。我们对Pcdh-j突变小鼠的分析 提供了第一个体内证据，证明原钙粘蛋白对脊椎动物CNS发育和玩耍至关重要 在建立神经元连接中的重要作用。然而，Pcdh-γ在突触形成过程中的功能 发展没有得到很好的定义，其分子作用机制也完全未知。我们计划 联合收割机的分子和遗传方法，以进一步了解Pcdh-y的功能。具体来说， 我们建议：1）研究Pcdh-γ各亚型的表达规律; 2）确定 Pcdh-y的多样性;以及3）识别和表征Pcdh-y的信令组分。实现 这些目标将阐明我们对精确性和复杂性的分子基础的理解， 大脑中的神经回路

The normal function of the brain relies on precise patterns of neuronal connections, and aberrant connectivity leads to human neurological and psychiatric disorders. The human brain consists of approximately100 billion neurons with trillions of synapses. Because of the enormous neuronal diversity and staggering synaptic complexity, very little is known about the molecular mechanisms that lead to the assembly of specific synapses in different neuronal types. Protocadherin (Pcdh) genes (14 Pcdh-a, 22 Pcdh-fi and 22 Pcdh-y in mouse) are attractive candidates for such a role because they can potentially generate a significant number of cell-surface "codes" through a combination of cell-specific promoter activation andcis- alternative splicing. It has been suggested that the distinct combinatorial Pcdh expression patterns might specify neuronal types and their connectivity. To evaluate their roles in neural development, we initiated functional analyses of these genes using genetically modified mice. Our analyses on Pcdh-j mutant mice provide the first in vivo evidence that protocadherins are essential for vertebrate CNS development and play an important role in establishing neuronal connectivity. However, Pcdh-y's function during synaptic development is not well defined and its molecular mechanisms of action are completely unknown. We plan to combine molecular and genetic approaches to further our understandingof Pcdh-y's functions.Specifically, we propose 1) to investigate the rules of expression for individual isoforms of Pcdh-y; 2) to define the role of Pcdh-y's diversity; and 3) to identify and characterize the signaling components of Pcdh-y. The attainment of these goals will shed light on our understandingof the molecular basis for the precision and complexity of neuronal circuitry in the brain.