Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara 630-0101, Japan.
J Cell Biol. 2010 Apr 5;189(1):159-70. doi: 10.1083/jcb.200908048. Epub 2010 Mar 29.
Once they have differentiated, cells retain their individual character and repress genes that are specifically expressed in other cell lineages, but how alternative fate choice is restricted during and/or after differentiation remains unclear. In the mammalian central nervous system, neurons, astrocytes, and oligodendrocytes are generated throughout life from common tripotent neural progenitor cells (NPCs). Bone morphogenetic proteins (BMPs) are well-known astrocyte-inducing cytokines. We show here that the expression of a transcriptional repressor, RE1 silencer of transcription (REST)/neuron-restrictive silencer factor (NRSF), is up-regulated and sustained by BMP signal activation in the course of astrocytic differentiation of NPCs, and restricts neuronal differentiation. We further show that, in differentiated astrocytes, endogenous REST/NRSF associates with various neuronal genes and that disruption of its function resulted in their derepression, thereby explaining how ectopic neuronal gene expression is prevented in cells with astrocytic traits. Collectively, our results suggest that REST/NRSF functions as a molecular regulator of the nonneuronal phenotype in astrocytes.
一旦细胞分化，它们就会保留各自的特征，并抑制在其他细胞谱系中特异性表达的基因，但在分化过程中或之后，如何限制替代命运选择尚不清楚。在哺乳动物中枢神经系统中，神经元、星形胶质细胞和少突胶质细胞在整个生命周期中都由常见的多能神经祖细胞（NPC）产生。骨形态发生蛋白（BMPs）是众所周知的星形胶质细胞诱导细胞因子。我们在这里表明，转录抑制因子 RE1 沉默转录因子（REST）/神经元限制沉默因子（NRSF）的表达在 NPC 星形胶质细胞分化过程中被 BMP 信号激活上调并维持，并限制神经元分化。我们进一步表明，在分化的星形胶质细胞中，内源性 REST/NRSF 与各种神经元基因结合，并且破坏其功能导致它们去抑制，从而解释了如何防止具有星形胶质细胞特征的细胞中异位神经元基因表达。总之，我们的研究结果表明，REST/NRSF 作为星形胶质细胞中非神经元表型的分子调节剂发挥作用。
