11月5日，《美國(guó)科學(xué)院院報(bào)》（PNAS）在線發(fā)表了中科院上海生科院神經(jīng)科學(xué)研究所熊志奇組的最新研究論文《X-連鎖的微管相關(guān)蛋白Mid1調(diào)控軸突的發(fā)育》,。這項(xiàng)工作揭示了位于X染色體上的Opitiz綜合征相關(guān)蛋白Mid1在神經(jīng)元軸突發(fā)育中的功能,，為了解Opitz綜合征的發(fā)病機(jī)理提供了線索。
智力障礙是一類較常見(jiàn)的人類神經(jīng)系統(tǒng)疾病,。在遺傳因素引起的智力障礙中,，相當(dāng)一部分是由X染色體上的基因突變或缺失所引起的。研究這些基因在神經(jīng)系統(tǒng)中的功能,，有助于了解智力障礙的產(chǎn)生原因,，對(duì)于診斷、預(yù)防這類疾病以及開(kāi)發(fā)有針對(duì)性的治療手段都具有重要意義,。
Mid1是一個(gè)與人類Opitz綜合征相關(guān)的X連鎖基因,，但目前對(duì)于其在神經(jīng)系統(tǒng)中的功能知之甚少。在這項(xiàng)研究中,，熊志奇研究組的陸婷佳,、陳任超等發(fā)現(xiàn)，Mid1參與調(diào)控了哺乳動(dòng)物皮層神經(jīng)元的軸突發(fā)育過(guò)程,。在神經(jīng)元中急性敲減Mid1的水平能夠促進(jìn)軸突的生長(zhǎng)與分枝,，并導(dǎo)致小鼠胼胝體軸突在對(duì)側(cè)皮層的正常投射模式被打亂。在Mid1基因敲除小鼠也發(fā)現(xiàn)了類似的異常,。進(jìn)一步的工作發(fā)現(xiàn),，Mid1是通過(guò)泛素化降解磷酸酶2A的催化亞基（PP2Ac）來(lái)實(shí)現(xiàn)對(duì)軸突生長(zhǎng)的控制：降低Mid1被下調(diào)的神經(jīng)元中過(guò)度積累的PP2Ac能夠回復(fù)Mid1敲減或敲除所引起的神經(jīng)元軸突生長(zhǎng)和投射異常。這項(xiàng)研究揭示了Mid1在軸突發(fā)育中的功能及其下游機(jī)制,，為尋找Opitz綜合征的發(fā)病機(jī)理提供了線索,。
該課題由研究生陸婷佳、陳任超及合作者在熊志奇研究員的指導(dǎo)下完成,。
這一工作得到了科技部“973”項(xiàng)目和國(guó)家自然科學(xué)基金的資助,。（生物谷Bioon.com）
生物谷推薦的英文摘要
Proceedings of the National Academy of the Sciences of the United States of America doi: 10.1073/pnas.1303687110
X-linked microtubule-associated protein， Mid1， regulates axon development
Tingjia Lua,，b,，1， Renchao Chena,，b,，1，2,， Timothy C. Coxc,，d， Randal X. Moldriche,， Nyoman Kurniawanf,， Guohe Tana， Jo K. Perryg,， Alan Ashworthg,， Perry F. Bartlette， Li Xua,， Jing Zhanga,， Bin Lua， Mingyue Wua,，b,， Qi Shena， Yuanyuan Liua,，b,， Linda J. Richardse，h,， and Zhiqi Xiong
Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS,， Midline-1 (MID1)， encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However,， how Mid1 functions during neural development is largely unknown. In this study,， we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation， resulting in a disruption of callosal axon projections in the contralateral cortex. In addition,， a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together,， these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS.
