SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron
SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron
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DOI：
10.1038/nature06270
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发表时间：
2007-11-15
期刊：
影响因子：
64.8
通讯作者：
Rosenfeld, Michael G.
中科院分区：
文献类型：
--
作者：
Jepsen, Kristen;Solum, Derek;Rosenfeld, Michael G.
一系列对维持神经干细胞状态至关重要的转录因子已被确定（1 - 3），但功能重要的辅阻遏物（4 - 7）在维持神经干细胞状态和早期神经发生中的作用仍不清楚。先前的研究已经描述了SMRT（也称为NCoR2，核受体辅阻遏物2）和NCoR在多种发育系统中的表达情况（8）；然而，SMRT辅阻遏物在神经发生中的具体作用仍有待确定。在此我们报道SMRT在前脑发育和维持神经干细胞状态中具有关键作用。对SMRT基因缺失小鼠的一系列标志物进行分析，揭示了SMRT在视黄酸依赖和Notch依赖的前脑发育过程中的功能需求。在分离的皮质祖细胞中，在没有任何配体的情况下，SMRT对于阻止视黄酸受体依赖的沿神经元途径的分化诱导至关重要。我们的数据显示，SMRT抑制含Jumonji结构域的基因JMJD3的表达，JMJD3是视黄酸受体的直接靶标，作为一种组蛋白H3三甲基K27去甲基化酶发挥作用，并且能够激活神经发生程序的特定成分。
A series of transcription factors critical for maintenance of the neural stem cell state have been identified(1-3), but the role of functionally important corepressors(4-7) in maintenance of the neural stem cell state and early neurogenesis remains unclear. Previous studies have characterized the expression of both SMRT ( also known as NCoR2, nuclear receptor co-repressor 2) and NCoR in a variety of developmental systems(8); however, the specific role of the SMRT corepressor in neurogenesis is still to be determined. Here we report a critical role for SMRT in forebrain development and in maintenance of the neural stem cell state. Analysis of a series of markers in SMRT-gene-deleted mice revealed the functional requirement of SMRT in the actions of both retinoic-acid-dependent and Notch-dependent forebrain development. In isolated cortical progenitor cells, SMRT was critical for preventing retinoic-acid-receptor- dependent induction of differentiation along a neuronal pathway in the absence of any ligand. Our data reveal that SMRT represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program.