Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth.
Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth.
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DOI：
10.1186/1741-7007-9-82
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发表时间：
2011-11-30
期刊：
影响因子：
5.4
通讯作者：
Henley JR
中科院分区：
文献类型：
--
作者：
Carlstrom LP;Hines JH;Henle SJ;Henley JR
细胞外微环境中的趋化因子通过作用于位于延伸轴突顶端的生长锥体来引导神经生长。生长锥延伸需要依赖细胞骨架的膜突起和与细胞外基质的动态黏附的协调，然而趋化因子如何调节这些事件仍然是一个悬而未决的问题。我们以前已经证明，抑制因子髓鞘相关糖蛋白(MAG)触发内细胞性移除生长锥体表面膜上的黏附受体β1-整合素，从而在化学排斥过程中负面重塑底物黏附。在这里，我们测试了神经营养素如何影响整合素粘连。我们报道，脑源性神经营养因子在刺激生长的过程中正向调节轴突生长锥体中底物黏附的形成，并阻止MAG去除β-1-整合素黏附。用脑源性神经营养因子处理非洲爪哇脊髓神经元可迅速触发β-1整合素聚集，并在生长锥体周围诱导新生的含纽蛋白的黏附复合体的动态形成。新生的β-1-整合素黏附的形成和BDNF2刺激轴突伸展都需要细胞质钙离子信号和细胞表面整合素的激活。在抑制轴突伸展的过程中，暴露于MAG可减少生长锥体内β-1-整合素粘连的数量。相反，BDNF诱导的粘连抵抗MAG的负性重塑，这与BDNF预处理对抗MAG抑制轴突延伸的能力有关。预先给予MAG可阻止脑源性神经营养因子诱导的β-1-整合素粘连的形成，并阻断脑源性神经营养因子对轴突延伸的刺激。综上所述，这些发现证明了神经营养素依赖的整合素黏附在生长锥体中的形成，并揭示了底物黏附的正调控因子如何阻断MAG的负面重塑和生长抑制效应。这种双向重塑可能允许生长锥快速调整与细胞外基质的粘附性，作为控制轴突延伸的一般机制。控制整合素内化和激活状态的技术对于克服创伤或神经退行性疾病后的局部抑制因素以促进再生神经生长可能是重要的。
Chemotropic factors in the extracellular microenvironment guide nerve growth by acting on the growth cone located at the tip of extending axons. Growth cone extension requires the coordination of cytoskeleton-dependent membrane protrusion and dynamic adhesion to the extracellular matrix, yet how chemotropic factors regulate these events remains an outstanding question. We demonstrated previously that the inhibitory factor myelin-associated glycoprotein (MAG) triggers endocytic removal of the adhesion receptor β1-integrin from the growth cone surface membrane to negatively remodel substrate adhesions during chemorepulsion. Here, we tested how a neurotrophin might affect integrin adhesions. We report that brain-derived neurotropic factor (BDNF) positively regulates the formation of substrate adhesions in axonal growth cones during stimulated outgrowth and prevents removal of β1-integrin adhesions by MAG. Treatment of Xenopus spinal neurons with BDNF rapidly triggered β1-integrin clustering and induced the dynamic formation of nascent vinculin-containing adhesion complexes in the growth cone periphery. Both the formation of nascent β1-integrin adhesions and the stimulation of axon extension by BDNF required cytoplasmic calcium ion signaling and integrin activation at the cell surface. Exposure to MAG decreased the number of β1-integrin adhesions in the growth cone during inhibition of axon extension. In contrast, the BDNF-induced adhesions were resistant to negative remodeling by MAG, correlating with the ability of BDNF pretreatment to counteract MAG-inhibition of axon extension. Pre-exposure to MAG prevented the BDNF-induced formation of β1-integrin adhesions and blocked the stimulation of axon extension by BDNF. Altogether, these findings demonstrate the neurotrophin-dependent formation of integrin-based adhesions in the growth cone and reveal how a positive regulator of substrate adhesions can block the negative remodeling and growth inhibitory effects of MAG. Such bidirectional remodeling may allow the growth cone to rapidly adjust adhesiveness to the extracellular matrix as a general mechanism for governing axon extension. Techniques for manipulating integrin internalization and activation state may be important for overcoming local inhibitory factors after traumatic injury or neurodegenerative disease to enhance regenerative nerve growth.
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5.3
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