Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate
Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate
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DOI：
10.1073/pnas.0603373103
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发表时间：
2006-06-20
影响因子：
11.1
通讯作者：
Xia, Zhengui
中科院分区：
文献类型：
--
作者：
Liu, Lidong;Cundiff, Paige;Xia, Zhengui
多能皮质祖细胞在发育过程中分化为神经元和神经胶质细胞，然而，对祖细胞向神经元命运的分化机制还不清楚。虽然外在和内在因素调节这一过程，很少有人知道激酶信号机制，直接神经元的命运。在这里，我们报告，细胞外信号调节激酶（ERK）5的表达和活跃的皮质祖细胞增殖。显性负性ERK 5或显性负性MAP激酶激酶5的慢病毒基因递送减少了培养中从大鼠皮质祖细胞产生的神经元的数量，而ERK 5的组成性激活增加了神经元的产生。此外，当皮质祖细胞与睫状神经营养因子，诱导早熟的胶质细胞分化，ERK 5激活仍然促进神经元的命运，同时抑制胶质细胞分化。我们的数据还表明，ERK 5不直接调节培养的皮质祖细胞的增殖或凋亡。我们的结论是，ERKS是必要的和足够的刺激皮质祖细胞神经元的产生。这些结果表明，在大脑发育过程中的ERK 5信号转导的一个以前未表征的功能，并提出了有趣的可能性，即外源性因素可能会指示皮质祖细胞成为神经元激活ERK 5通路。
Multipotent cortical progenitor cells differentiate into neurons and glial cells during development; however, mechanisms governing the specification of progenitors to a neuronal fate are not well understood. Although both extrinsic and intrinsic factors regulate this process, little is known about kinase signaling mechanisms that direct neuronal fate. Here, we report that extracellular signal-regulated kinase (ERK)5 is expressed and active in proliferating cortical progenitors. Lentiviral gene delivery of a dominant negative ERK5 or dominant negative MAP kinase kinase 5 reduced the number of neurons generated from rat cortical progenitor cells in culture, whereas constitutive activation of ERK5 increased the production of neurons. Furthermore, when cortical progenitor cells were treated with ciliary neurotrophic factor, which induces precocious glial differentiation, ERK5 activation still promoted neuronal fate while suppressing glial differentiation. Our data also indicate that ERK5 does not directly regulate proliferation or apoptosis of cultured cortical progenitors. We conclude that ERKS is necessary and sufficient to stimulate the generation of neurons from cortical progenitors. These results suggest a previously uncharacterized function for ERK5 signaling during brain development and raise the interesting possibility that extrinsic factors may instruct cortical progenitors to become neurons by activating the ERK5 pathway.