Control of Cortical Axon Elongation by a GABA-Driven Ca2+/Calmodulin-Dependent Protein Kinase Cascade
Control of Cortical Axon Elongation by a GABA-Driven Ca2+/Calmodulin-Dependent Protein Kinase Cascade
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DOI：
10.1523/jneurosci.3018-09.2009
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发表时间：
2009-10-28
影响因子：
5.3
通讯作者：
Bito, Haruhiko
中科院分区：
文献类型：
--
作者：
Ageta-Ishihara, Natsumi;Takemoto-Kimura, Sayaka;Bito, Haruhiko
Ca2+ 信号传导在轴突和树突生长过程中发挥着重要作用。然而，Ca2+ 的升高是否以及如何升高可能触发并促进长程皮质连接的发展仍然知之甚少。在这里，我们证明 Ca2+/钙调蛋白依赖性蛋白激酶激酶 (CaMKK)-CaMKI 级联的两个独立分支，CaMKK-CaMKI α 和 CaMKK-CaMKI γ，分别关键地协调皮质神经元的轴突和树突形态发生。轴突特异性形态表型需要 CaMKI 的弥漫性细胞质定位和显着的 α 同工型特异性激酶活性。出乎意料的是，用蝇蕈醇（一种 GABA(A) 受体激动剂）治疗选择性刺激轴突伸长，但不刺激树突伸长，并且 CaMKK-CaMKI α 级联关键介导了这种轴突作用。与这些发现一致的是，在早期大脑发育过程中，CaMKI α的体内敲低显着损害了终末轴突延伸，从而扰乱了半球间胼胝体投射到对侧皮质的细化。因此，我们的研究结果表明，GABA 驱动的 CaMKK-CaMKI α 级联作为精确皮质轴突寻路的关键机制，具有新的作用，这是一个可能有助于微调中枢神经系统围产期发育过程中半球间连接形成的重要过程。
Ca2+ signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca2+ rises may trigger and contribute to the development of long-range cortical connections remains mostly unknown. Here, we demonstrate that two separate limbs of the Ca2+/calmodulin-dependent protein kinase kinase (CaMKK)-CaMKI cascades, CaMKK-CaMKI alpha and CaMKK-CaMKI gamma, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly alpha-isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA(A) receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK-CaMKI alpha cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKI alpha significantly impaired the terminal axonal extension and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK-CaMKI alpha cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process that may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the CNS.