AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress.
AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress.
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AMP 激活蛋白激酶 (AMPK) 活性不是神经元发育所必需的，但在代谢应激期间调节轴突发生。
DOI：
10.1073/pnas.1013660108
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发表时间：
2011
影响因子：
11.1
通讯作者：
Polleux,Franck
中科院分区：
文献类型：
--
作者：
Williams,Tyisha;Courchet,Julien;Viollet,Benoit;Brenman,JayE;Polleux,Franck
哺乳动物大脑的连接需要数十亿神经元的协同产生和迁移，以及轴突和树突的形成。LKB1/Par4激酶是体内皮层发育过程中轴突形成所必需的，部分通过其激活SAD-A/B激酶的能力。LKB1是一种主激酶，可磷酸化并激活至少11种其他丝氨酸/苏氨酸激酶，包括代谢传感器amp活化蛋白激酶（AMPK），它定义了激酶的这一分支。最近一项利用AMPK β1调控亚基基因诱捕等位基因的研究表明，AMPK的催化活性对于包括神经发生和神经元存活在内的正常大脑发育是必需的。我们使用了一种产生无AMPKα1/α2皮质神经元的基因功能丧失方法，以证明AMPK的催化活性对皮质神经发生、神经元迁移、极化或存活并不需要。然而，我们发现应用二甲双胍或AICAR，有效的AMPK激活剂，以AMPK依赖的方式抑制轴突生长和轴突生长。我们发现，AMPK过度激活介导的轴突生长抑制需要tsc1 /2介导的雷帕霉素靶蛋白（mTOR）信号通路的抑制。我们的研究结果表明，AMPK的催化活性不是体内早期神经发育所必需的，但其在代谢应激期间的过度激活以mtor依赖的方式损害神经元极化。
Mammalian brain connectivity requires the coordinated production and migration of billions of neurons and the formation of axons and dendrites. The LKB1/Par4 kinase is required for axon formation during cortical development in vivo partially through its ability to activate SAD-A/B kinases. LKB1 is a master kinase phosphorylating and activating at least 11 other serine/threonine kinases including the metabolic sensor AMP-activated protein kinase (AMPK), which defines this branch of the kinome. A recent study using a gene-trap allele of the β1 regulatory subunit of AMPK suggested that AMPK catalytic activity is required for proper brain development including neurogenesis and neuronal survival. We used a genetic loss-of-function approach producing AMPKα1/α2-null cortical neurons to demonstrate that AMPK catalytic activity is not required for cortical neurogenesis, neuronal migration, polarization, or survival. However, we found that application of metformin or AICAR, potent AMPK activators, inhibit axogenesis and axon growth in an AMPK-dependent manner. We show that inhibition of axon growth mediated by AMPK overactivation requires TSC1/2-mediated inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. Our results demonstrate that AMPK catalytic activity is not required for early neural development in vivo but its overactivation during metabolic stress impairs neuronal polarization in a mTOR-dependent manner.