Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
Cell Rep. 2013 Sep 12;4(5):996-1009. doi: 10.1016/j.celrep.2013.07.045. Epub 2013 Aug 29.
Neuronal migration is essential for nervous system development in all organisms and is regulated in the nematode, C. elegans, by signaling pathways that are conserved in humans. Here, we demonstrate that the insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to regulate the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. When signaling is reduced, DAF-16 is activated and promotes migration; conversely, when signaling is enhanced, DAF-16 is inactivated, and migration is inhibited. We show that DAF-16 acts nonautonomously in the hypodermis to promote HSN migration. Furthermore, we identify PAK-1, a p21-activated kinase, as a downstream mediator of insulin/IGF-1-DAF-16 signaling in the nonautonomous control of HSN migration. Because a FOXO-Pak1 pathway was recently shown to regulate mammalian neuronal polarity, our findings indicate that the roles of FOXO and Pak1 in neuronal migration are most likely conserved from C. elegans to higher organisms.
神经元迁移对于所有生物体的神经系统发育都是必不可少的，在秀丽隐杆线虫中，通过与人类保守的信号通路来调节。在这里，我们证明胰岛素/ IGF-1-PI3K 信号通路调节 DAF-16/FOXO 转录因子的活性，以调节秀丽隐杆线虫胚胎发生过程中雌雄同体特异性神经元（HSN）的前向迁移。当信号减少时，DAF-16 被激活并促进迁移；相反，当信号增强时，DAF-16 失活，迁移受到抑制。我们表明 DAF-16 在真皮层中发挥非自主作用以促进 HSN 迁移。此外，我们确定 PAK-1，一种 p21 激活激酶，作为胰岛素/ IGF-1-DAF-16 信号在 HSN 迁移的非自主控制中的下游介质。由于最近表明 FOXO-Pak1 途径调节哺乳动物神经元极性，我们的发现表明 FOXO 和 Pak1 在神经元迁移中的作用很可能从秀丽隐杆线虫到高等生物是保守的。
