RasGRF1 mediates brain-derived neurotrophic factor-induced axonal growth in primary cultured cortical neurons.
RasGRF1 mediates brain-derived neurotrophic factor-induced axonal growth in primary cultured cortical neurons.
复制标题
RasGRF1 介导原代培养的皮质神经元中脑源性神经营养因子诱导的轴突生长。
DOI：
10.1016/j.bbrep.2018.11.011
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发表时间：
2019
影响因子：
2.7
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
Umeda K.;Negishi;M.;Katoh;H.
神经元形态的适当发育和调控对于建立功能性神经元回路和实现中枢神经系统的高级脑功能具有重要意义。R-Ras是小gtpase Ras家族的一员，在轴突形态的调控中起着至关重要的作用，包括生长、分支和引导。gtp结合激活的R-Ras通过与其下游效应物的相互作用重组肌动蛋白丝和微管，从而精确控制轴突形态。然而，我们对神经元中R-Ras激活的上游调控机制知之甚少。在本研究中，我们发现脑源性神经营养因子（BDNF）对内源性R-Ras激活具有积极作用，并促进R-Ras介导的轴突生长。RNA干扰敲除和过表达实验表明，rras的鸟嘌呤核苷酸交换因子（GEF） RasGRF1参与bdnf诱导的R-Ras活化和促进轴突生长。蛋白激酶A磷酸化RasGRF1的Ser916/898位点是充分激活其GEF活性和促进Ras信号传导所必需的。我们观察到BDNF处理显著增加了这种磷酸化。我们的研究结果表明，BDNF是R-Ras激活的关键外源调节因子之一，而RasGRF1是BDNF诱导的R-Ras激活和R-Ras介导的轴突形态调节的内在关键介质。
The appropriate development and regulation of neuronal morphology are important to establish functional neuronal circuits and enable higher brain function of the central nervous system. R-Ras, a member of the Ras family of small GTPases, plays crucial roles in the regulation of axonal morphology, including outgrowth, branching, and guidance. GTP-bound activated R-Ras reorganizes actin filaments and microtubules through interactions with its downstream effectors, leading to the precise control of axonal morphology. However, little is known about the upstream regulatory mechanisms for R-Ras activation in neurons. In this study, we found that brain-derived neurotrophic factor (BDNF) has a positive effect on endogenous R-Ras activation and promotes R-Ras-mediated axonal growth. RNA interference knockdown and overexpression experiments revealed that RasGRF1, a guanine nucleotide exchange factor (GEF) for R-Ras, is involved in BDNF-induced R-Ras activation and the promotion of axonal growth. Phosphorylation of RasGRF1 by protein kinase A at Ser916/898 is needed for the full activation of its GEF activity and to facilitate Ras signaling. We observed that BDNF treatment markedly increased this phosphorylation. Our results suggest that BDNF is one of the critical extrinsic regulators for R-Ras activation, and that RasGRF1 is an intrinsic key mediator for BDNF-induced R-Ras activation and R-Ras-mediated axonal morphological regulation.