Guidance of Postural Motoneurons Requires MAPK/ERK Signaling Downstream of Fibroblast Growth Factor Receptor 1
Guidance of Postural Motoneurons Requires MAPK/ERK Signaling Downstream of Fibroblast Growth Factor Receptor 1
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DOI：
10.1523/jneurosci.4932-09.2010
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发表时间：
2010-05-12
影响因子：
5.3
通讯作者：
Rafuse, Victor F.
中科院分区：
文献类型：
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作者：
Soundararajan, Prabakaran;Fawcett, James P.;Rafuse, Victor F.
确定适当的轴突指导所必需的细胞内信号传导途径是具有挑战性的，因为用于研究这些事件的许多CNS群体包含多种细胞类型。在这里，我们解决了这个问题，通过使用小鼠胚胎干细胞（ES），定向分化成运动神经元的人口，专门支配轴上肌肉[内侧正中运动柱（MMCm）运动神经元]。这些ES细胞衍生的MMCm运动神经元，像它们的内源性对应物一样，表达成纤维细胞生长因子受体1（FGFR 1），并选择性地向轴向营养因子FGF 8延伸轴突。与野生型MMCm运动神经元不同，FGFR 1（-/-）MMCm运动神经元在移植到鸡胚神经管中时显示出导向缺陷。此外，FGFR 1的激活通过促分裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）选择性地发出信号，用于体外适当的指导，而在移植的或内源性鸡MMCm细胞中组成型活性MAPK/ERK的过表达导致体内指导缺陷。这些结果表明，MAPK/ERK激活下游的FGFR 1是必要的MMCm运动轴突的指导和ES细胞衍生的神经元提供了一个重要的工具，解剖轴突指导所需的细胞内途径。
Identification of intracellular signaling pathways necessary for appropriate axon guidance is challenging because many CNS populations used to study these events contain multiple cell types. Here, we resolve this issue by using mouse embryonic stem (ES) cells that were directed to differentiate into a population of motoneurons that exclusively innervate epaxial muscles [medial median motor column (MMCm) motoneurons]. These ES cell-derived MMCm motoneurons, like their endogenous counterparts, express fibroblast growth factor receptor 1 (FGFR1) and selectively extend axons toward the epaxial trophin FGF8. Unlike wild-type MMCm motoneurons, FGFR1(-/-) MMCm motoneurons show guidance defects when transplanted into the neural tube of chick embryos. Furthermore, activation of FGFR1 selectively signals through mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) for appropriate guidance in vitro, whereas overexpression of constitutively active MAPK/ERK in transplanted, or endogenous chick, MMCm cells causes guidance defects in vivo. These results indicate that MAPK/ERK activation downstream of FGFR1 is necessary for MMCm motor axon guidance and that ES cell-derived neurons provide an important tool for dissecting intracellular pathways required for axon guidance.