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 Jun 11;8(1):8811. doi: 10.1038/s41598-018-27081-1.
The characteristic six layers of the mammalian neocortex develop sequentially as neurons are generated by neural progenitors and subsequently migrate past older neurons to their final position in the cortical plate. One of the earliest steps of neuronal differentiation is the formation of an axon. Small GTPases play essential roles during this process by regulating cytoskeletal dynamics and intracellular trafficking. While the function of GTPases has been studied extensively in cultured neurons and in vivo much less is known about their upstream regulators. Here we show that Arhgef7 (also called βPix or Cool1) is essential for axon formation during cortical development. The loss of Arhgef7 results in an extensive loss of axons in cultured neurons and in the developing cortex. Arhgef7 is a guanine-nucleotide exchange factor (GEF) for Cdc42, a GTPase that has a central role in directing the formation of axons during brain development. However, active Cdc42 was not able to rescue the knockdown of Arhgef7. We show that Arhgef7 interacts with the GTPase TC10 that is closely related to Cdc42. Expression of active TC10 can restore the ability to extend axons in Arhgef7-deficient neurons. Our results identify an essential role of Arhgef7 during neuronal development that promotes axon formation upstream of TC10.
哺乳动物新皮层的特征六层结构是随着神经祖细胞产生的神经元的迁移而依次发育的，这些神经元会越过较老的神经元，最终到达皮质板的最终位置。神经元分化的最早步骤之一是轴突的形成。小分子 GTP 酶通过调节细胞骨架动力学和细胞内运输在这个过程中发挥着重要作用。虽然 GTP 酶的功能已在培养的神经元中得到了广泛研究，但在体内，关于其上游调节剂的了解要少得多。在这里，我们表明 Arhgef7（也称为βPix 或 Cool1）在皮质发育过程中的轴突形成中是必不可少的。Arhgef7 的缺失会导致培养神经元和发育中的皮质中广泛的轴突丧失。Arhgef7 是 Cdc42 的鸟嘌呤核苷酸交换因子（GEF），Cdc42 在大脑发育过程中指导轴突形成中起着核心作用。然而，活性 Cdc42 不能挽救 Arhgef7 敲低的效果。我们表明，Arhgef7 与 GTP 酶 TC10 相互作用，TC10 与 Cdc42 密切相关。表达活性 TC10 可以恢复 Arhgef7 缺陷神经元中延伸轴突的能力。我们的结果确定了 Arhgef7 在神经元发育过程中的重要作用，它在上游促进了 TC10 的轴突形成。
