Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
J Neurosci. 2013 Jan 2;33(1):327-33. doi: 10.1523/JNEUROSCI.2509-12.2013.
Pyramidal neurons have a highly polarized dendritic morphology, characterized by one long apical dendrite and multiple short basal dendrites. They function as the primary excitatory cells of the mammalian prefrontal cortex and the corticospinal tract. However, the molecular mechanisms underlying the development of polarized dendrite morphology in pyramidal neurons remain poorly understood. Here, we report that the Angelman syndrome (AS) protein ubiquitin-protein ligase E3A (Ube3a) plays an important role in specifying the polarization of pyramidal neuron dendritic arbors in mice. shRNA-mediated downregulation of Ube3a selectively inhibited apical dendrite outgrowth and resulted in impaired dendrite polarity, which could be rescued by coexpressing mouse Ube3a isoform 2, but not isoform 1 or 3. Ube3a knockdown also disrupted the polarized distribution of the Golgi apparatus, a well established cellular mechanism for asymmetric dendritic growth in pyramidal neurons. Furthermore, downregulation of Ube3a completely blocked Reelin-induced rapid deployment of Golgi into dendrite. Consistently, we also observed selective inhibition of apical dendrite outgrowth in pyramidal neurons in a mouse model of AS. Overall, these results show that Ube3a is required for the specification of the apical dendrites and dendrite polarization in pyramidal neurons, and suggest a novel pathological mechanism for AS.
锥体神经元具有高度极化的树突形态，其特征是一个长的顶树突和多个短的基底树突。它们作为哺乳动物前额叶皮层和皮质脊髓束的主要兴奋性细胞发挥作用。然而，锥体神经元极化树突形态发育的分子机制仍知之甚少。在这里，我们报告 Angelman 综合征（AS）蛋白泛素蛋白连接酶 E3A（Ube3a）在小鼠中特异性指定锥体神经元树突树突极性中发挥重要作用。shRNA 介导的 Ube3a 下调选择性抑制顶树突生长，导致树突极性受损，这可以通过共表达小鼠 Ube3a 同种型 2 来挽救，但同种型 1 或 3 则不行。Ube3a 下调还破坏了高尔基器的极化分布，高尔基器是锥体神经元中不对称树突生长的一种成熟的细胞机制。此外，下调 Ube3a 完全阻断了 Reelin 诱导的高尔基器快速向树突的部署。一致地，我们还观察到 AS 小鼠模型中锥体神经元的顶树突生长选择性抑制。总的来说，这些结果表明 Ube3a 是锥体神经元中顶树突和树突极性指定所必需的，并为 AS 提供了一种新的病理机制。
