PURPOSE Recent findings indicate the significant contribution of urokinase and urokinase receptor (uPA and uPAR) in the processes of nerve regeneration, however, their role in axonal growth and branching is unclear. Using a 3D model of mouse Dorsal Root Ganglia (DRG) explants, differentiated into neurons Neuro 2a cells and transgenic mice lacking the urokinase gene, we studied the involvement of the uPA/uPAR system in the neural cell migration, neurite outgrowth, elongation and branching. RESULTS uPA and uPAR are expressed in the growth cones of axons. Using an ex vivo model of DRG explants in Matrigel we have found that uPA inhibition attenuates neural cell migration and axonal growth, pointing to an important role of urokinase in these processes. Apparently, uPA mediates its effects through its specific receptor uPAR: anti-uPAR antibody, which blocks the uPA binding to uPAR, stimulates axon branching and attenuates neural cell migration from DRG explants. Simultaneous inhibition of uPA and uPAR almost completely prevents the axonal outgrowth from explants into the Matrigels. Experiments in vitro using Neuro 2a cells differentiated into neurons demonstrate that administration of exogenous uPA increases the neurite growth rate (elongation), most likely via the interaction of uPA with uPAR. Blocking of uPAR stimulates neurite formation and enhances branching of preexisting neurites. The results obtained on DRG explants from transgenic mice lacking uPA gene support the assumption that uPA stimulates neurite growth via uPA/uPAR interaction and uPAR role in axons branching and neural cell migration. CONCLUSIONS The uPA/uPAR system plays an essential role in neural cell migration, axonal growth and branching.

中文翻译：

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尿激酶和尿激酶受体参与神经元迁移，轴突生长和分支的调节。

目的最近的发现表明，尿激酶和尿激酶受体（uPA和uPAR）在神经再生过程中有重要作用，但是，它们在轴突生长和分支中的作用尚不清楚。使用小鼠背根神经节（DRG）外植体，分化为神经元Neuro 2a细胞和缺乏尿激酶基因的转基因小鼠的3D模型，我们研究了uPA / uPAR系统在神经细胞迁移，神经突向外生长，伸长和分支中的作用。结果uPA和uPAR在轴突的生长锥中表达。使用Matrigel中DRG外植体的离体模型，我们发现uPA抑制作用会减弱神经细胞迁移和轴突生长，这表明尿激酶在这些过程中具有重要作用。显然，uPA通过其特异性受体uPAR介导其作用：抗uPAR抗体，阻断uPA与uPAR的结合，刺激轴突分支并减弱DRG外植体中神经细胞的迁移。同时抑制uPA和uPAR几乎可以完全防止轴突向外植体进入基质胶。使用分化为神经元的Neuro 2a细胞进行的体外实验表明，外源性uPA的施用最有可能通过uPA与uPAR的相互作用来增加神经突生长速率（伸长）。uPAR的阻断刺激神经突的形成并增强先前存在的神经突的分支。从缺乏uPA基因的转基因小鼠的DRG外植体获得的结果支持以下假设：uPA通过uPA / uPAR相互作用以及uPAR在轴突分支和神经细胞迁移中的作用刺激神经突生长。结论uPA / uPAR系统在神经细胞迁移中起着至关重要的作用，