2012年11月21日 訊 /生物谷BIOON/ --大腦皮層是最復(fù)雜的結(jié)構(gòu),調(diào)控我們的意識(shí),情感以及語(yǔ)言等功能,。為了履行這些職能,,它是由多樣化的皮質(zhì)神經(jīng)元的神經(jīng)細(xì)胞組成,而這些神經(jīng)細(xì)胞會(huì)受到許多神經(jīng)系統(tǒng)疾病的影響,。
近日,,由Pierre Vanderhaeghen領(lǐng)導(dǎo)的研究小組發(fā)現(xiàn)了大腦發(fā)育的一個(gè)關(guān)鍵基因 BCL6,研究證實(shí)了BCL6是胚胎大腦發(fā)育過(guò)程中皮質(zhì)神經(jīng)元生成的一個(gè)關(guān)鍵因素,。這項(xiàng)研究發(fā)表在11月18日的Nature Neuroscience雜志上,。
博士Luca Tiberi通過(guò)搜索確定BCL6是可以調(diào)節(jié)神經(jīng)細(xì)胞的生成,是小鼠胚胎干細(xì)胞神經(jīng)分化的因素,。他們發(fā)現(xiàn)過(guò)表達(dá)BCL6導(dǎo)致神經(jīng)干細(xì)胞大規(guī)模演變成大腦皮質(zhì)神經(jīng)元細(xì)胞,。這一發(fā)現(xiàn)令人吃驚,因?yàn)锽CL6其實(shí)是一個(gè)眾所周知的致癌基因,。然而,,這個(gè)基因在大腦發(fā)育中確切作用是不甚明了的。為了驗(yàn)證他們的有趣的觀察,,科學(xué)家研究了BCL6基因被破壞的轉(zhuǎn)基因小鼠模型,。
他們發(fā)現(xiàn),這些突變小鼠大腦皮質(zhì)明顯較小,,同時(shí)含有較少的神經(jīng)細(xì)胞,。因此,這些數(shù)據(jù)表明,,BCL6是正常大腦發(fā)育過(guò)程中大腦皮質(zhì)神經(jīng)元正常產(chǎn)生的關(guān)鍵因子,。
他們還闡明了潛在的分子機(jī)制,并表明BCL6是與SIRT1相互作用來(lái)抑制Notch途徑,,而后者涉及到神經(jīng)干細(xì)胞的自我更新,。這種抑制現(xiàn)象是“后生”的,使得皮層神經(jīng)元不可逆的分化成神經(jīng)干細(xì)胞,。
這項(xiàng)最新研究成果不僅對(duì)發(fā)育和干細(xì)胞神經(jīng)生物學(xué),同時(shí)也給腫瘤生物學(xué)帶來(lái)了新的問(wèn)題和觀點(diǎn),。首先,,它證實(shí)了BCL6是皮質(zhì)神經(jīng)細(xì)胞生成的關(guān)鍵因子。其次,,它闡明了神經(jīng)干細(xì)胞一種新的分化分子機(jī)制,,這對(duì)我們理解是什么控制神經(jīng)干細(xì)胞的分化與自我更新具有重要意義。
最后,,研究還揭示了參與無(wú)數(shù)的正常和病理過(guò)程的三個(gè)共同因子:BCL6,,一個(gè)癌基因主要負(fù)責(zé)血細(xì)胞癌,Sirt1涉及老化,,阿爾茨海默氏病,,代謝和糖尿病等,,Notch途徑參與大腦和心臟發(fā)育或癌變等過(guò)程。這些基因在以往研究中是沒(méi)被證明存在互相交流,,現(xiàn)在這項(xiàng)研究幫助我們能更好地理解生物學(xué)和病理學(xué),,開發(fā)新的治療方法。(生物谷:Bioon.com)
doi:10.1038/nn.3264
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BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets.
Luca Tiberi, Jelle van den Ameele, Jordane Dimidschstein, Julie Piccirilli, David Gall, Adèle Herpoel, Angéline Bilheu, Jerome Bonnefont, Michelina Iacovino, Michael Kyba, Tristan Bouschet, Pierre Vanderhaeghen.
During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signaling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition. We identified Bcl6, an oncogene, as encoding a proneurogenic factor that is required for proper neurogenesis of the mouse cerebral cortex. BCL6 promoted the neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. BCL6 triggered exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD+-dependent deacetylase Sirt1, which was required for BCL6-dependent neurogenesis. The resulting epigenetic silencing of Hes5 led to neuronal differentiation despite active Notch signaling. Our findings suggest a role for BCL6 in neurogenesis and uncover Notch-BCL6-Sirt1 interactions that may affect other aspects of physiology and disease.