Discovery of long-range inhibitory signaling to ensure single axon formation.
Discovery of long-range inhibitory signaling to ensure single axon formation.
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DOI：
10.1038/s41467-017-00044-2
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发表时间：
2017-06-26
影响因子：
16.6
通讯作者：
Kaibuchi K
中科院分区：
文献类型：
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作者：
Takano T;Wu M;Nakamuta S;Naoki H;Ishizawa N;Namba T;Watanabe T;Xu C;Hamaguchi T;Yura Y;Amano M;Hahn KM;Kaibuchi K
神经发育中一个长期存在的问题是神经元如何从普通的未成熟神经突发育成单个轴突和多个树突。长距离的抑制信号从生长轴突被假设为防止其他未成熟的神经突的生长，并分化成树突，但这种抑制信号的存在和性质仍然未知。在这里，我们表明，轴突生长神经营养因子-3引发远程抑制神经突起的生长，通过长距离的钙波，这是从生长的轴突传递到细胞体。这些Ca 2+波通过钙/钙调蛋白依赖性蛋白激酶I增加细胞体中的RhoA活性。Rho激酶的光遗传学控制与计算模型相结合揭示了活性Rho激酶扩散到生长中的其他未成熟神经突并抑制它们的生长。从机制上讲，钙调蛋白依赖性蛋白激酶I磷酸化RhoA特异性GEF，GEF-H1，其磷酸化增强其GEF活性。因此，我们的研究结果表明，由Ca ~（2+）波介导的长程抑制信号是负责神经元极化。新出现的证据表明，肠道微生物群影响大脑的免疫功能，并可能在神经系统疾病中发挥作用。在这里，作者提供了来自果蝇模型的体内证据，该模型支持肠道微生物群在调节阿尔茨海默病进展中的作用。
A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca2+ waves, which are delivered from the growing axon to the cell body. These Ca2+ waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca2+ wave is responsible for neuronal polarization. Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer’s disease.