Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway
Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway
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DOI：
10.1038/nn.2662
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发表时间：
2010-11-01
影响因子：
25
通讯作者：
Hazan, Jamile
中科院分区：
文献类型：
--
作者：
Fassier, Coralie;Hutt, James A.;Hazan, Jamile
为了更好地了解遗传性痉挛性截瘫（HSP），我们通过分析发育中的斑马鱼的功能丧失和功能获得表型，表征了一种经常与幼年型HSP有关的蛋白阿特拉斯丁的功能。我们发现，atlastin （atl1）基因的敲低会导致幼虫活动能力的严重下降，在此之前会出现脊髓运动轴突的异常结构，并与骨形态发生蛋白（BMP）信号通路的大幅上调有关。过表达分析证实，atlastin抑制BMP信号传导。在斑马鱼脊髓神经元的原代培养中，在沿神经突分布的晚期内体中，阿特拉斯蛋白部分地与I型BMP受体共定位，这表明阿特拉斯蛋白可能调节BMP受体的运输。最后，基因或药物抑制BMP信号足以挽救atl1变形体的活动能力丧失和脊髓运动轴突缺陷，强调了微调BMP信号平衡对脊椎动物运动轴突结构和稳定性的重要性。
To better understand hereditary spastic paraplegia (HSP), we characterized the function of atlastin, a protein that is frequently involved in juvenile forms of HSP, by analyzing loss- and gain-of-function phenotypes in the developing zebrafish. We found that knockdown of the gene for atlastin (atl1) caused a severe decrease in larval mobility that was preceded by abnormal architecture of spinal motor axons and was associated with a substantial upregulation of the bone morphogenetic protein (BMP) signaling pathway. Overexpression analyses confirmed that atlastin inhibits BMP signaling. In primary cultures of zebrafish spinal neurons, Atlastin partially colocalized with type I BMP receptors in late endosomes distributed along neurites, which suggests that atlastin may regulate BMP receptor trafficking. Finally, genetic or pharmacological inhibition of BMP signaling was sufficient to rescue the loss of mobility and spinal motor axon defects of atl1 morphants, emphasizing the importance of fine-tuning the balance of BMP signaling for vertebrate motor axon architecture and stability.