Total Expression and Dual Gene-regulatory Mechanisms Maintained in Deletions and Duplications of the Pcdha Cluster
Total Expression and Dual Gene-regulatory Mechanisms Maintained in Deletions and Duplications of the Pcdha Cluster
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DOI：
10.1074/jbc.m109.046938
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发表时间：
2009-11-13
影响因子：
4.8
通讯作者：
Yagi, Takeshi
中科院分区：
文献类型：
--
作者：
Noguchi, Yukiko;Hirabayashi, Takahiro;Yagi, Takeshi
聚簇型原钙粘蛋白α (Pcdha)基因在脊椎动物大脑中表达，编码多种膜蛋白，其功能涉及轴突投射和学习记忆。Pcdha簇由14个串联排列的基因组成（Pcdha1-Pcdha12、Pcdhac1和Pcdhac2，从5‘到3’）。每个第一外显子（可变外显子）都是从其自身的启动子转录而来，并拼接到所有Pcdha基因共有的恒定外显子上。小脑浦肯野细胞显示Pcdha的双重表达模式。在单个浦肯野细胞中，簇中不同的5‘基因Pcdha1-12是随机表达的，而3’基因Pcdhac1和Pcdhac2是组成性表达的。为了阐明Pcdha簇的基因组结构与其在浦肯野细胞中的表达之间的关系，我们删除或复制了多个变量外显子，并分析了Pcdha基因在小鼠脑中的表达。在所有突变小鼠中，恒定外显子的转录水平和双重表达模式得以维持。在缺失突变体中，缺失的基因被剩余的可变外显子灵活地补偿。另一方面，在重复突变体中，重复基因的水平被削减了。这些结果表明，Pcdha基因作为一个簇单位被全面调控，并且在缺失或复制的突变等位基因中，随机和组成性驱动Pcdha基因表达的调控因子是完整的。这种双重调控机制可能在神经元的多样性和基本功能中发挥重要作用。
The clustered protocadherin-alpha (Pcdha) genes, which are expressed in the vertebrate brain, encode diverse membrane proteins whose functions are involved in axonal projection and in learning and memory. The Pcdha cluster consists of 14 tandemly arranged genes (Pcdha1-Pcdha12, Pcdhac1, and Pcdhac2, from 5' to 3'). Each first exon ( the variable exons) is transcribed from its own promoter, and spliced to the constant exons, which are common to all the Pcdha genes. Cerebellar Purkinje cells show dual expression patterns for Pcdha. In individual Purkinje cells, different sets of the 5' genes in the cluster, Pcdha1-12, are randomly expressed, whereas both 3' genes, Pcdhac1 and Pcdhac2, are expressed constitutively. To elucidate the relationship between the genomic structure of the Pcdha cluster and their expression in Purkinje cells, we deleted or duplicated multiple variable exons and analyzed the expression of Pcdha genes in the mouse brain. In all mutant mice, transcript levels of the constant exons and the dual expression patterns were maintained. In the deletion mutants, the missing genes were flexibly compensated by the remaining variable exons. On the other hand, in duplication mutants, the levels of the duplicated genes were trimmed. These results indicate that the Pcdha genes are comprehensively regulated as a cluster unit, and that the regulators that randomly and constitutively drive Pcdha gene expression are intact in the deleted or duplicated mutant alleles. These dual regulatory mechanisms may play important roles in the diversity and fundamental functions of neurons.