Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands.
Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences (UIPS), Science for Life, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, Netherlands.
Sci Adv. 2022 Nov 4;8(44):eabo2343. doi: 10.1126/sciadv.abo2343.
The polarization of neurons into axons and dendrites depends on extracellular cues, intracellular signaling, cytoskeletal rearrangements, and polarized transport, but the interplay between these processes during polarization remains unresolved. Here, we show that axon specification is determined by differences in microtubule network mobility between neurites, regulated by Rho guanosine triphosphatases (GTPases) and extracellular cues. In developing neurons, retrograde microtubule flow prevents the entry of the axon-selective motor protein Kinesin-1 into most neurites. Using inducible assays to control microtubule network flow, we demonstrate that local inhibition of microtubule mobility is sufficient to guide Kinesin-1 into a specific neurite, whereas long-term global inhibition induces the formation of multiple axons. We furthermore show that extracellular mechanical cues and intracellular Rho GTPase signaling control the local differences in microtubule network flow. These results reveal a novel cytoskeletal mechanism for neuronal polarization.
神经元向轴突和树突的极化取决于细胞外线索、细胞内信号、细胞骨架重排和极化运输，但极化过程中这些过程之间的相互作用仍未解决。在这里，我们表明，轴突的特化取决于突起之间微管网络流动性的差异，这种差异受 Rho 鸟苷三磷酸酶（GTPase）和细胞外线索的调节。在发育中的神经元中，逆行微管流阻止了轴突选择性运动蛋白 Kinesin-1 进入大多数突起。使用可诱导的测定来控制微管网络流，我们证明局部抑制微管流动性足以将 Kinesin-1 引导到特定的突起中，而长期的全局抑制则诱导多个轴突的形成。我们还表明，细胞外机械线索和细胞内 Rho GTPase 信号控制微管网络流动的局部差异。这些结果揭示了神经元极化的一种新的细胞骨架机制。
