1月2日,，Journal of Neuroscience發(fā)表了神經(jīng)所熊志奇研究組題為“Angelman綜合征蛋白Ube3a調(diào)控錐體神經(jīng)元樹突的極性發(fā)育”的研究成果,。該工作由博士生苗盛及合作者在熊志奇研究員的指導(dǎo)下完成,。
作為哺乳動物皮層的主要興奮性神經(jīng)元,，錐體神經(jīng)元具有高度極化的樹突形態(tài),其樹突由一支較長的頂樹突和若干較短的基樹突所構(gòu)成,。這兩類樹突在結(jié)構(gòu)上的特化決定了它們在信息整合上的功能特異性,然而,，目前對樹突形態(tài)極化發(fā)育的分子機(jī)制知之甚少,。Angleman綜合征是由UBE3A基因的表達(dá)缺失所導(dǎo)致的一種嚴(yán)重的神經(jīng)系統(tǒng)發(fā)育性疾病,， 患者表現(xiàn)發(fā)育遲緩和智力低下,、癲癇、共濟(jì)失調(diào),、語言障礙等癥狀,。在這項研究中，作者以小鼠為模式動物,，運(yùn)用RNA干擾,、胚胎電轉(zhuǎn)、單細(xì)胞biocytin染料標(biāo)記等手段,，揭示了Angelman綜合征蛋白Ube3a在樹突極性發(fā)育中的嶄新功能,。Ube3a基因在胚胎期和生后早期的大腦中有高水平表達(dá)。使用胚胎電轉(zhuǎn)的手段降低其在錐體神經(jīng)元中的表達(dá)水平,，從生后第三天開始,，選擇性地抑制了的錐體神經(jīng)元頂樹突的優(yōu)勢性生長而不并未影響基樹突的正常發(fā)育，最終導(dǎo)致了樹突極性的減弱。該表型可以特異性的被廣泛分布于細(xì)胞質(zhì)中的Ube3a亞型II所挽救,，而不能被缺乏E3連接酶活性的亞型I或是在細(xì)胞核中富集的亞型III挽救,，提示細(xì)胞質(zhì)中Ube3a的連接酶活性對樹突正常極化發(fā)育是必需的。此外,，Ube3a的表達(dá)下調(diào)不但破壞了高爾基體趨向頂樹突的極性分布,，而且完全抑制了Reelin信號通路所引起的高爾基體向頂樹突的快速進(jìn)入，證明Ube3a參與了高爾基體在胞內(nèi)的定向（Golgi positioning）與運(yùn)動 (Golgi motility) 的調(diào)節(jié),。在Angelman綜合征模型小鼠中,，錐體神經(jīng)元頂樹突的優(yōu)勢性生長也發(fā)生了異常。
該工作表明廣泛分布于細(xì)胞質(zhì)中的Ube3a亞型II對于高爾基體形態(tài)功能的維持,、錐體神經(jīng)元頂樹突的特化以及樹突的極性化發(fā)育都是必需的,。提示錐體神經(jīng)元因樹突極性減弱所引起的神經(jīng)環(huán)路異常可能是Angelman綜合征患者智力低下的結(jié)構(gòu)基礎(chǔ),。
該研究工作受到科技部973計劃和國家自然科學(xué)基金委員會,、中國科學(xué)院等基金資助。(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.
