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Functional significance of isoform diversification in the protocadherin gamma gene cluster

机译：原钙粘蛋白γ基因簇中同工型多样化的功能意义

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摘要

The mammalian Protocadherin (Pcdh) alpha, beta, and gamma gene clusters encode a large family of cadherin-like transmembrane proteins that are differentially expressed in individual neurons. The 22 isoforms of the Pcdhg gene cluster are diversified into A-, B-, and C-types, and the C-type isoforms differ from all other clustered Pcdhs in sequence and expression. Here, we show that mice lacking the three C-type isoforms are phenotypically indistinguishable from the Pcdhg null mutants, displaying virtually identical cellular and synaptic alterations resulting from neuronal apoptosis. By contrast, mice lacking three A-type isoforms exhibit no detectable phenotypes. Remarkably, however, genetically blocking apoptosis rescues the neonatal lethality of the C-type isoform knockouts, but not that of the Pcdhg null mutants. We conclude that the role of the Pcdhg gene cluster in neuronal survival is primarily, if not specifically, mediated by its C-type isoforms, whereas a separate role essential for postnatal development, likely in neuronal wiring, requires isoform diversity. Previous studies have indicated that the protocadherin gamma gene cluster is required for neuronal survival. Here, Chen et al. show that this role appears to be specifically mediated by the C-type genes, revealing the functional divergence of protocadherin isoforms.
机译：哺乳动物原钙粘蛋白（Pcdh）α，β和γ基因簇编码大量钙粘蛋白样跨膜蛋白家族，这些蛋白在单个神经元中差异表达。 Pcdhg基因簇的22个同工型被分为A型，B型和C型，并且C型同工型在序列和表达上与所有其他成簇的Pcdhs不同。在这里，我们显示缺少三种C型同种型的小鼠与Pcdhg null突变型在表型上没有区别，显示出由神经元凋亡导致的几乎相同的细胞和突触改变。相反，缺乏三种A型同工型的小鼠则没有可检测的表型。然而，值得注意的是，基因阻断凋亡可以挽救C型同工型敲除的新生儿致死性，但不能挽救Pcdhg null突变体的致死性。我们得出的结论是，Pcdhg基因簇在神经元存活中的作用主要是（如果不是特别地）由其C型同工型介导，而产后发育所必需的单独作用（可能在神经元接线中）则需要同工型多样性。先前的研究表明，原钙粘蛋白γ基因簇是神经元生存所必需的。在这里，Chen等。表明这种作用似乎是由C型基因特异性介导的，揭示了原钙粘蛋白同工型的功能差异。

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