The Transcription Factor Serum Response Factor Stimulates Axon Regeneration through Cytoplasmic Localization and Cofilin Interaction
The Transcription Factor Serum Response Factor Stimulates Axon Regeneration through Cytoplasmic Localization and Cofilin Interaction
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DOI：
10.1523/jneurosci.3029-13.2013
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发表时间：
2013-11-27
影响因子：
5.3
通讯作者：
Knoell, Bernd
中科院分区：
文献类型：
--
作者：
Stern, Sina;Haverkamp, Stephanie;Knoell, Bernd
轴突损伤产生生长惰性收缩球与动态细胞骨架的性质，是严重受损。轴突再生的一个主要目的是将“冻结”的收缩球转化为积极进展的生长锥。在这里，我们报告说，鼠血清反应因子（SRF），基因调节连接到肌动蛋白细胞骨架，调节生长锥肌动蛋白轴突再生过程中的动力学。在再生能力的面部运动神经元，Srf缺失抑制轴突再生。在野生型小鼠神经损伤后，SRF从细胞核易位到细胞质，这表明细胞质SRF在轴突再生中的功能。事实上，腺病毒过表达胞质SRF（SRF-Delta NLS-GFP）刺激轴突发芽和面神经再生在体内。在原代中枢和外周神经元中，SRF-Δ NLS-GFP刺激神经突生长、分支形成和生长锥形态。此外，我们发现了SRF和肌动蛋白切断因子cofilin在体内轴突再生过程中的联系。面神经轴突切断术增加了总的cofilin丰度和核定位的磷酸化cofilin在一个亚群的损伤运动神经元。在表达SRF-Delta NLS-GFP的运动神经元中，轴突切断后P-切丝蛋白的这种胞质到核的易位减少。最后，我们证明了细胞质SRF和cofilin形成了一个相互调节单位。胞质SRF的过表达降低了cofilin的磷酸化，反之亦然：cofilin的过表达抑制了SRF的磷酸化。因此，由SRF和cofilin组成的调节环可能参与重新激活生长惰性收缩球中的肌动蛋白动力学并促进轴突再生。
Axonal injury generates growth inert retraction bulbs with dynamic cytoskeletal properties that are severely compromised. Conversion of "frozen" retraction bulbs into actively progressing growth cones is a major aim in axon regeneration. Here we report that murine serum response factor (SRF), a gene regulator linked to the actin cytoskeleton, modulates growth cone actin dynamics during axon regeneration. In regeneration-competent facial motoneurons, Srf deletion inhibited axonal regeneration. In wild-type mice after nerve injury, SRF translocated from the nucleus to the cytoplasm, suggesting a cytoplasmic SRF function in axonal regeneration. Indeed, adenoviral overexpression of cytoplasmic SRF (SRF-Delta NLS-GFP) stimulated axonal sprouting and facial nerve regeneration in vivo. In primary central and peripheral neurons, SRF-Delta NLS-GFP stimulated neurite outgrowth, branch formation, and growth cone morphology. Furthermore, we uncovered a link between SRF and the actin-severing factor cofilin during axonal regeneration in vivo. Facial nerve axotomy increased the total cofilin abundance and also nuclear localization of phosphorylated cofilin in a subpopulation of lesioned motoneurons. This cytoplasmic-to-nucleus translocation of P-cofilin upon axotomy was reduced in motoneurons expressing SRF-Delta NLS-GFP. Finally, we demonstrate that cytoplasmic SRF and cofilin formed a reciprocal regulatory unit. Overexpression of cytoplasmic SRF reduced cofilin phosphorylation and vice versa: overexpression of cofilin inhibited SRF phosphorylation. Therefore, a regulatory loop consisting of SRF and cofilin might take part in reactivating actin dynamics in growth-inert retraction bulbs and facilitating axon regeneration.