Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells
Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells
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DOI：
10.1128/mcb.02435-06
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发表时间：
2007-07-01
影响因子：
5.3
通讯作者：
Taga, Tetsuya
中科院分区：
文献类型：
--
作者：
Fukuda, Shinji;Abematsu, Masahiko;Taga, Tetsuya
星形胶质细胞在脑发育和损伤反应中起重要作用。转录因子STAT3和Smad1分别被白血病抑制因子（LIF）和骨形态发生蛋白2 （BMP2）激活，与辅激活因子p300形成复合物，协同诱导神经上皮细胞（NECs）中的星形胶质细胞（K. Nakashima， M. Yanagisawa， H. Arakawa， N. Kimura， T. Hisatsune， M. Kawabata， K. Miyazono， T. Taga, Science, 284:479482, 1999）。然而，在决定神经干细胞命运的过程中，星形胶质细胞形成的机制仍然难以捉摸。本研究发现，LIF通过STAT3激活诱导BMP2的表达，进而导致Smad1的激活，从而有效促进NECs的星形胶质细胞分化。BMP拮抗剂Noggin通过抑制NECs产生的BMP来消除lif诱导的小细胞活化和星形胶质细胞形成。缺乏细胞因子信号传导抑制因子3 (SOCS3) （STAT3的负调节因子）的NECs在LIF激活后很容易分化为星形胶质细胞，这不仅是因为STAT3的持续激活，还因为随之而来的Smadl的激活。我们的研究表明，一种新的liff触发的正调节回路可以增强星形胶质细胞的发生。
Astrocytes play important roles in brain development and injury response. Transcription factors STAT3 and Smad1, activated by leukemia inhibitory factor (LIF) and bone morphogenetic protein 2 (BMP2), respectively, form a complex with the coactivator p300 to synergistically induce astrocytes from neuroepithelial cells (NECs) (K. Nakashima, M. Yanagisawa, H. Arakawa, N. Kimura, T. Hisatsune, M. Kawabata, K. Miyazono, and T. Taga, Science 284:479482, 1999). However, the mechanisms that govern astrogliogenesis during the determination of the fate of neural stem cells remain elusive. Here we found that LIF induces expression of BMP2 via STAT3 activation and leads to the consequent activation of Smad1 to efficiently promote astrogliogenic differentiation of NECs. The BMP antagonist Noggin abrogated LIF-induced Smadl activation and astrogliogenesis by inhibiting BMPs produced by NECs. NECs deficient in suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3, readily differentiated into astrocytes upon activation by LIF not only due to sustained activation of STAT3 but also because of the consequent activation of Smadl. Our study suggests a novel LIF-triggered positive regulatory loop that enhances astrogliogenesis.