Regulation of axon formation by Rab10 and Arhgef7

Rab10 和 Arhgef7 对轴突形成的调节

• 批准号: 516614182
• 负责人: Professor Dr. Andreas Püschel
• 金额: --
• 依托单位: Institut für Molekulare Zellbiologie (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/516614182?language=en
• 关键词: Regulation; axon; formation; Rab10; Arhgef7

Neurons are highly polarized cells that establish molecularly and functionally distinct axonal and somato-dendritic compartments. Newborn postmitotic neurons initially exhibit a multi-polar morphology with several undifferentiated processes. They establish their polarized morphology by selecting one of their neurites as the axon. Neuronal polarization happens spontaneously in cultures of hippocampal neurons from the embryonic brain of rodents without requiring an input from patterned extrinsic signals. Axon extension depends the expansion of the plasma membrane by the exocytosis of specialized plasmalemma precursor vesicles (PPVs) in the growth cone. It is facilitated by the polarization of intracellular transport into the nascent axon that provides the material for growth. PPVs are present in all neurites before polarization but their exocytosis occurs preferentially in the growth cone of the nascent axon. The formation of axons is orchestrated by GTPases that regulate cytoskeletal dynamics as well as intracellular transport and exocytosis. PPVs are characterized by the presence of the GTPase Rab10 that is detectable in all neurites of unpolarized neurons but becomes enriched in the axon upon polarization. Rab10 is essential for axon formation and its knockdown prevents neuronal polarization. Prior to their exocytosis, PPVs are tethered at the plasma membrane of the growth cone by the octameric exocyst complex that is essential for axon formation. The exocyst complex is recruited to the membrane by the GTPase TC10. We have identified Arhgef7 as a GEF that activates TC10 during axon formation. When Arhgef7 is inactivated by a knockout or a knockdown, neurons fail to extend axons. In this project we will investigate the role of Rab10 GEFs, Rab10 and Argef7 for the trafficking and exocytosis of PPVs during axon formation.

神经元是高度极化的细胞，它们建立分子和功能上不同的轴突和体树突区室。新生的有丝分裂后神经元最初表现出具有多个未分化过程的多极形态。它们通过选择其中一个神经突作为轴突来建立极化形态。在啮齿动物胚胎大脑的海马神经元培养物中，神经元极化自发发生，不需要模式化的外在信号输入。轴突延伸取决于生长锥中特殊质膜前体囊泡 (PPV) 的胞吐作用导致的质膜扩张。细胞内运输的极化促进了新生轴突的形成，为生长提供了材料。 PPV 在极化前存在于所有神经突中，但它们的胞吐作用优先发生在新生轴突的生长锥中。轴突的形成是由 GTP 酶精心策划的，GTP 酶调节细胞骨架动力学以及细胞内运输和胞吐作用。 PPV 的特征是存在 GTPase Rab10，其在非极化神经元的所有神经突中均可检测到，但在极化后在轴突中富集。 Rab10 对于轴突形成至关重要，其敲低可防止神经元极化。在进行胞吐作用之前，PPV 被八聚体胞吐复合物束缚在生长锥的质膜上，而八聚体胞吐复合物对于轴突形成至关重要。外囊复合物被 GTPase TC10 募集到膜上。我们已经确定 Arhgef7 是在轴突形成过程中激活 TC10 的 GEF。当 Arhgef7 因敲除或敲低而失活时，神经元无法延伸轴突。在本项目中，我们将研究 Rab10 GEF、Rab10 和 Argef7 在轴突形成过程中 PPV 运输和胞吐作用中的作用。