Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität, Schloßplatz 5, D-48149, Münster, Germany.
Cells-in-Motion Cluster of Excellence, University of Münster, D-48149, Münster, Germany.
Sci Rep. 2018 Oct 23;8(1):15647. doi: 10.1038/s41598-018-34092-5.
The highly conserved Rap1 GTPases perform essential functions during neuronal development. They are required for the polarity of neuronal progenitors and neurons as well as for neuronal migration in the embryonic brain. Neuronal polarization and axon formation depend on the precise temporal and spatial regulation of Rap1 activity by guanine nucleotide exchange factors (GEFs) and GTPases-activating proteins (GAPs). Several Rap1 GEFs have been identified that direct the formation of axons during cortical and hippocampal development in vivo and in cultured neurons. However little is known about the GAPs that limit the activity of Rap1 GTPases during neuronal development. Here we investigate the function of Sema3A and Plexin-A1 as a regulator of Rap1 GTPases during the polarization of hippocampal neurons. Sema3A was shown to suppress axon formation when neurons are cultured on a patterned substrate. Plexin-A1 functions as the signal-transducing subunit of receptors for Sema3A and displays GAP activity for Rap1 GTPases. We show that Sema3A and Plexin-A1 suppress the formation of supernumerary axons in cultured neurons, which depends on Rap1 GTPases.
高度保守的 Rap1 GTPases 在神经元发育过程中发挥着重要的功能。它们对于神经元前体细胞和神经元的极性以及胚胎大脑中的神经元迁移是必需的。神经元的极化和轴突的形成依赖于 Rap1 活性的精确的时空调节，这是由鸟嘌呤核苷酸交换因子（GEFs）和 GTPases-activating proteins（GAPs）来完成的。已经鉴定出几种 Rap1 GEFs，它们在体内和培养的神经元中指导皮质和海马发育过程中轴突的形成。然而，对于在神经元发育过程中限制 Rap1 GTPases 活性的 GAPs 知之甚少。在这里，我们研究了 Sema3A 和 Plexin-A1 在海马神经元极化过程中作为 Rap1 GTPases 调节剂的功能。研究表明，当神经元在图案化的基质上培养时，Sema3A 会抑制轴突的形成。Plexin-A1 作为 Sema3A 的信号转导亚基，并显示出对 Rap1 GTPases 的 GAP 活性。我们表明，Sema3A 和 Plexin-A1 抑制了培养神经元中超数轴突的形成，这依赖于 Rap1 GTPases。
