Protocadherin signaling in the central nervous system

描述（由申请人提供）：大脑的正常功能依赖于神经元连接的精确模式，异常连接导致人类神经和精神疾病。人类大脑由大约1000亿个神经元和数万亿个突触组成。由于神经元的巨大多样性和惊人的突触复杂性，导致不同类型神经元中特定突触组装的分子机制知之甚少。原钙粘蛋白（Pcdh）基因（小鼠中的14 Pcdh-a、22 Pcdh-fi和22 Pcdh-y）是发挥这种作用的有吸引力的候选者，因为它们可以通过细胞特异性启动子激活和顺式选择性剪接的组合产生大量的细胞表面“代码”。有研究表明，不同的Pcdh组合表达模式可能指定了神经元类型及其连接。为了评估它们在神经发育中的作用，我们使用转基因小鼠对这些基因进行了功能分析。我们对Pcdh-j突变小鼠的分析首次提供了活体证据，证明原钙粘蛋白对脊椎动物中枢神经系统的发育至关重要，并在建立神经元连接中发挥重要作用。然而，Pcdh-y在突触发育过程中的功能尚不清楚，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进一步了解Pcdh-y的功能。具体来说，我们建议1)研究Pcdh-y的单个同工异构体的表达规则；2)明确Pcdh-y多样性的作用；3)识别和表征Pcdh-y的信号传导成分。这些目标的实现将有助于我们理解大脑中神经元回路的精确和复杂性的分子基础。

DESCRIPTION (provided by applicant): 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 approximately 100 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 and cis- 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 understanding of 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 understanding of the molecular basis for the precision and complexity of neuronal circuitry in the brain.