1月2日，Journal of Neuroscience发表了神经所熊志奇研究组题为“Angelman综合征蛋白Ube3a调控锥体神经元树突的极性发育”的研究成果。该工作由博士生苗盛及合作者在熊志奇研究员的指导下完成。
作为哺乳动物皮层的主要兴奋性神经元，锥体神经元具有高度极化的树突形态,其树突由一支较长的顶树突和若干较短的基树突所构成。这两类树突在结构上的特化决定了它们在信息整合上的功能特异性,然而，目前对树突形态极化发育的分子机制知之甚少。Angleman综合征是由UBE3A基因的表达缺失所导致的一种严重的神经系统发育性疾病， 患者表现发育迟缓和智力低下、癫痫、共济失调、语言障碍等症状。在这项研究中，作者以小鼠为模式动物，运用RNA干扰、胚胎电转、单细胞biocytin染料标记等手段，揭示了Angelman综合征蛋白Ube3a在树突极性发育中的崭新功能。Ube3a基因在胚胎期和生后早期的大脑中有高水平表达。使用胚胎电转的手段降低其在锥体神经元中的表达水平，从生后第三天开始，选择性地抑制了的锥体神经元顶树突的优势性生长而不并未影响基树突的正常发育，最终导致了树突极性的减弱。该表型可以特异性的被广泛分布于细胞质中的Ube3a亚型II所挽救，而不能被缺乏E3连接酶活性的亚型I或是在细胞核中富集的亚型III挽救，提示细胞质中Ube3a的连接酶活性对树突正常极化发育是必需的。此外，Ube3a的表达下调不但破坏了高尔基体趋向顶树突的极性分布，而且完全抑制了Reelin信号通路所引起的高尔基体向顶树突的快速进入，证明Ube3a参与了高尔基体在胞内的定向（Golgi positioning）与运动 (Golgi motility) 的调节。在Angelman综合征模型小鼠中，锥体神经元顶树突的优势性生长也发生了异常。
该工作表明广泛分布于细胞质中的Ube3a亚型II对于高尔基体形态功能的维持、锥体神经元顶树突的特化以及树突的极性化发育都是必需的。提示锥体神经元因树突极性减弱所引起的神经环路异常可能是Angelman综合征患者智力低下的结构基础。
该研究工作受到科技部973计划和国家自然科学基金委员会、中国科学院等基金资助。(生物谷Bioon.com)
doi: 10.1523/JNEUROSCI.2509-12.2013
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The Angelman Syndrome Protein Ube3a Is Required for Polarized Dendrite Morphogenesis in Pyramidal Neurons
Sheng Miao1, Renchao Chen1, Jiahao Ye1, Guo-He Tan1, Shuai Li1, Jing Zhang1, Yong-hui Jiang2, and Zhi-Qi Xiong1
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.
