Protocadherin signaling in the central nervous system

大脑的正常功能依赖于神经元连接的精确模式，以及 连通性会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。因为巨大的神经元多样性和 令人震惊的突触复杂性，人们对导致突触的分子机制知之甚少 不同神经元类型中特定突触的组装。原钙粘附素(Pcdh)基因(14个Pcdh-a，22个Pcdh-fi 和鼠标中的22 Pcdh-y)是这样一个角色的有吸引力的候选人，因为他们可能会产生一个 大量的细胞表面“密码”通过细胞特异性启动子的激活和顺式作用的结合-- 另一种拼接。有人认为，不同的组合Pcdh表达模式可能 指定神经元类型及其连通性。为了评估它们在神经发育中的作用，我们发起了 利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 提供第一个体内证据表明原钙粘附素对脊椎动物中枢神经系统的发育和发挥是必不可少的 在建立神经元连接方面起着重要作用。然而，Pcdh-y在突触中的作用 发育没有明确的定义，其分子作用机制也完全未知。我们计划 结合分子和遗传方法来加深我们对Pcdh-y功能的理解。具体地说， 我们建议1)研究Pcdh-y各个亚型的表达规则；2)定义Pcdh-y的作用 Pcdh-y的多样性；以及3)识别和表征Pcdh-y的信号成分。达到了 这些目标将有助于我们对分子基础的精确度和复杂性的理解 大脑中的神经元回路。

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.