Brill Monika S, Kleele Tatjana, Ruschkies Laura, Wang Mengzhe, Marahori Natalia A, Reuter Miriam S, Hausrat Torben J, Weigand Emily, Fisher Matthew, Ahles Andrea, Engelhardt Stefan, Bishop Derron L, Kneussel Matthias, Misgeld Thomas
Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
Neuron. 2016 Nov 23;92(4):845-856. doi: 10.1016/j.neuron.2016.09.049. Epub 2016 Oct 20.
Developmental axon remodeling is characterized by the selective removal of branches from axon arbors. The mechanisms that underlie such branch loss are largely unknown. Additionally, how neuronal resources are specifically assigned to the branches of remodeling arbors is not understood. Here we show that axon branch loss at the developing mouse neuromuscular junction is mediated by branch-specific microtubule severing, which results in local disassembly of the microtubule cytoskeleton and loss of axonal transport in branches that will subsequently dismantle. Accordingly, pharmacological microtubule stabilization delays neuromuscular synapse elimination. This branch-specific disassembly of the cytoskeleton appears to be mediated by the microtubule-severing enzyme spastin, which is dysfunctional in some forms of upper motor neuron disease. Our results demonstrate a physiological role for a neurodegeneration-associated modulator of the cytoskeleton, reveal unexpected cell biology of branch-specific axon plasticity and underscore the mechanistic similarities of axon loss in development and disease.
发育性轴突重塑的特征是从轴突分支中选择性去除分支。这种分支丢失背后的机制在很大程度上尚不清楚。此外，神经元资源如何具体分配到重塑分支上也不为人所知。在这里，我们表明，发育中的小鼠神经肌肉接头处的轴突分支丢失是由分支特异性微管切断介导的，这导致微管细胞骨架的局部解体以及随后将被拆解的分支中轴突运输的丧失。因此，药物性微管稳定可延迟神经肌肉突触消除。这种细胞骨架的分支特异性解体似乎是由微管切断酶痉挛素介导的，痉挛素在某些形式的上运动神经元疾病中功能失调。我们的结果证明了一种与神经退行性变相关的细胞骨架调节剂的生理作用，揭示了分支特异性轴突可塑性的意外细胞生物学现象，并强调了发育和疾病中轴突丢失的机制相似性。
