Department of Neurodegenerative Disease, Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology, London WC1N 3BG, United Kingdom.
J Neurosci. 2011 Apr 6;31(14):5483-94. doi: 10.1523/JNEUROSCI.5244-10.2011.
The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system.
细胞质动力蛋白复合物对于所有真核细胞来说都是至关重要的，它可以沿着细胞内的微管运输各种必需的货物。该复合物在神经元中也发挥着更为专业化的作用。该复合物由 11 种相互作用的蛋白质以及与外部衔接蛋白、调节蛋白和货物结合的蛋白质组成。尽管细胞质动力蛋白复合物非常重要，但我们对每个组成蛋白的作用了解甚少，在哺乳动物中，很少有突变体存在，这使得我们无法在整个生物体的背景下探索动力蛋白控制的过程缺陷的影响。在这里，我们采用了小鼠（Mus musculus）的基因驱动方法来分析一个亚基——动力蛋白轻链 1（Dync1li1）的作用。我们惊讶地发现，该蛋白中的 N235Y 点突变导致神经元发育异常，这可以从发育中的皮质的体内研究和电生理功能分析中得到证实。此外，突变小鼠表现出焦虑增加，这是首次将动力蛋白功能与哺乳动物的行为表型联系起来。这些结果表明，动力蛋白控制的过程在哺乳动物神经系统的正确发育和功能中起着重要作用。
