CNRS UMR 7224, Physiopathologie des Maladies du Système Nerveux Central, Paris, France.
Nat Neurosci. 2010 Nov;13(11):1380-7. doi: 10.1038/nn.2662. Epub 2010 Oct 10.
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.
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中的功能丧失和获得功能表型，研究了常涉及青少年 HSP 形式的蛋白 atlastin 的功能。我们发现，atlastin（atl1）基因的敲低导致幼虫运动能力严重下降，这之前是脊髓运动轴突结构异常，并与骨形态发生蛋白（BMP）信号通路的大量上调有关。过表达分析证实，atlastin 抑制 BMP 信号。在斑马鱼脊髓神经元的原代培养物中，Atlastin 与沿神经突分布的晚期内体中的 I 型 BMP 受体部分共定位，这表明 Atlastin 可能调节 BMP 受体运输。最后，BMP 信号的遗传或药理学抑制足以挽救 atl1 形态发生缺陷体的运动能力丧失和脊髓运动轴突缺陷，这强调了精细调节 BMP 信号平衡对于脊椎动物运动轴突结构和稳定性的重要性。
