脑中某些区域生成新神经细胞的机制
2009-05-26 20:37:38   来源：   作者：  评论：0 点击：

现在人们已经接受了成年脑有生长新细胞的弹性这样一个观点，但在脑中某些区域一生中维持神经生成的分子机制尚不清楚。影响基因表达的一大因素是染色质（核 苷酸与构成染色体的蛋白组成的复合物）的结构。

现在，Lim等人发现，在出生后小鼠的脑中，染色质重塑因子基因“Mll1 (mixed lineage leukaemia 1)”促使神经干细胞形成神经元，而在没有Mll1的情况下，同样的干细胞则会产生神经胶质细胞，它们是在神经系统中主要起辅助作用的非神经元细胞。 Mll1部分是通过激发下游基因Dlx2起作用的，后者是脑室下区（subventricular zone）中神经生成的一个关键调控因子。

Nature458, 529-533 (26 March 2009) | doi :10.1038/nature07726 ; Received 23 July 2007; Accepted 15 December 2008; Published online 11 February 2009

Chromatin remodelling factor Mll1is essential for neurogenesis from postnatal neural stem cells

Daniel A. Lim 1 , 2 , 3 , 8 , Yin-Cheng Huang 1 , 2 , 8 , 9 , Tomek Swigut 4 , Anika L. Mirick 5 , Jose Manuel Garcia-Verdugo 6 , 7 , Joanna Wysocka 4 , Patricia Ernst 5 & Arturo Alvarez-Buylla 1 , 2

Epigenetic mechanisms that maintain neurogenesis throughout adult life remain poorly understood . Trithorax group (trxG) and Polycomb group (PcG) gene products are part of an evolutionarily conserved chromatin remodelling system that activate or silence gene expression, respectively . Although PcG member Bmi1has been shown to be required for postnatal neural stem cell self-renewal , the role of trxG genes remains unknown. Here we show that the trxG member Mll1( mixed-lineage leukaemia 1) is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1-deficient cells, early proneural Mash1 and gliogenic Olig2expression are preserved, but Dlx2, a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2can rescue neurogenesis in Mll1-deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2is a direct target of MLL in subventricular zone cells. In differentiating wild-type subventricular zone cells, Mash1, Olig2and Dlx2loci have high levels of histone 3 trimethylated at lysine 4 (H3K4me3), consistent with their transcription. In contrast, in Mll1-deficient subventricular zone cells, chromatin at Dlx2is bivalently marked by both H3K4me3 and histone 3 trimethylated at lysine 27 (H3K27me3), and the Dlx2gene fails to properly activate. These data support a model in which Mll1is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis.