大腦神經(jīng)發(fā)育要經(jīng)歷神經(jīng)干細(xì)胞分化,，神經(jīng)元遷移，突觸形成以及神經(jīng)環(huán)路的建立與重塑等過程,，最終形成一個(gè)復(fù)雜的功能神經(jīng)網(wǎng)絡(luò),。大腦發(fā)育異常可導(dǎo)致智力低下,，癲癇和多種精神疾病,。神經(jīng)元遷移在正常大腦皮層結(jié)構(gòu)建立和功能神經(jīng)網(wǎng)絡(luò)形成過程中起關(guān)鍵作用。遷移神經(jīng)元具有典型的雙極（bipolar）結(jié)構(gòu),，分別是leading和trailing processes. Leading process在幾十年前就被發(fā)現(xiàn)具有從粗到細(xì)的結(jié)構(gòu),，在靠近胞體的位置最粗（Cytoplasmic dilation）。最近研究還表明,，F(xiàn)-actin 在Cytoplasmic dilation中聚集并調(diào)控神經(jīng)元遷移過程。然而,，相關(guān)的分子機(jī)制一直未明了,。
許執(zhí)恒課題組通過胚胎腦內(nèi)電轉(zhuǎn)技術(shù)和多種細(xì)胞生物學(xué)手段，發(fā)現(xiàn)JNK信號(hào)通路的支架蛋白—POSH和小G蛋白—Rac1是大腦發(fā)育過程中神經(jīng)元遷移所必需的,，另外,，他們發(fā)現(xiàn)敲降POSH或Rac1的表達(dá)均可導(dǎo)致遷移神經(jīng)元的leading process在靠近胞體的位置無法形成具有從粗到細(xì)的結(jié)構(gòu)。進(jìn)一步研究表明,，POSH通過調(diào)控Rac1的膜定位來調(diào)控Cytoplasmic dilation形成以及F-actin 在leading process中的組裝,，進(jìn)而調(diào)控神經(jīng)元遷移過程，從而闡明了Cytoplasmic dilation形成的分子機(jī)制,。同時(shí),，該研究解決了另外一個(gè)長(zhǎng)期懸而未決的科學(xué)問題——細(xì)胞內(nèi)活化Rac1的定位機(jī)制,。該研究為深入探索大腦發(fā)育的分子機(jī)制提供了堅(jiān)實(shí)基礎(chǔ)。
相關(guān)研究結(jié)果以Full Article的形式發(fā)表在Cell子刊—Cell Reports上,。該項(xiàng)工作受到科技部,，中科院及國(guó)家自然科學(xué)基金委項(xiàng)目的資助。（生物谷Bioon.com）
doi:10.1016/j.celrep.2012.08.007
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POSH Localizes Activated Rac1 to Control the Formation of Cytoplasmic Dilation of the Leading Process and Neuronal Migration
Tao Yang, Yiming Sun, Feng Zhang, Yuangang Zhu, Lei Shi, Huashun Li and Zhiheng Xu.
The formation of proximal cytoplasmic dilation in the leading process (PCDLP) of migratory neocortical neurons is crucial for somal translocation and neuronal migration, processes that require the elaborate coordination of F-actin dynamics, centrosomal movement, and nucleokinesis. However, the underlying molecular mechanisms remain poorly understood. Here, we show that the Rac1-interacting scaffold protein POSH is essential for neuronal migration in vivo. We demonstrate that POSH is concentrated in the PCDLP and that knockdown of POSH impairs PCDLP formation, centrosome translocation, and nucleokinesis. Furthermore, POSH colocalizes with F-actin and the activated form of Rac1. Knockdown of POSH impairs F-actin assembly and delocalizes activated Rac1. Interference of Rac1 activity also disrupts F-actin assembly and PCDLP formation and perturbs neuronal migration. Thus, we have uncovered a mechanism by which POSH regulates the localization of activated Rac1 and F-actin assembly to control PCDLP formation and subsequent somal translocation of migratory neurons.
