Rac1 Guides Porf-2 to Wnt Pathway to Mediate Neural Stem Cell Proliferation.
Rac1 Guides Porf-2 to Wnt Pathway to Mediate Neural Stem Cell Proliferation.
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Rac1 引导 Porf-2 进入 Wnt 通路介导神经干细胞增殖
DOI：
10.3389/fnmol.2017.00172
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发表时间：
2017
影响因子：
4.8
通讯作者：
Feng DF
中科院分区：
文献类型：
--
作者：
Yang XT;Huang GH;Li HJ;Sun ZL;Xu NJ;Feng DF
视前调节因子2（Porf-2）对神经干细胞（NSCs）的抗增殖作用的分子和细胞机制仍不清楚。在这里，我们发现，Porf-2抑制Ras相关的C3肉毒杆菌毒素底物1（Rac 1）蛋白在大鼠海马神经干细胞的活性。Rac 1活性的降低损害了β-catenin的核转位，最终导致NSC增殖的抑制。Porf-2敲除增强了神经干细胞的增殖，但在Rac 1或Wnt的小分子抑制剂存在的情况下则不然。同时，Rac 1或Wnt小分子激活剂可拮抗Porf-2过表达对NSCs增殖的抑制作用。通过建立大鼠视神经损伤模型，我们观察到Porf-2基因敲低可促进视功能的恢复。特别是，大鼠视神经损伤导致Wnt家族成员3a（Wnt 3a）蛋白表达增加，我们发现其负责增强Porf-2敲低诱导的NSCs增殖。这些结果表明Porf-2通过Rac 1-Wnt/β-catenin途径抑制神经干细胞的增殖。因此，Porf-2可能是视神经损伤恢复和治疗的有趣靶点。
The molecular and cellular mechanisms underlying the anti-proliferative effects of preoptic regulator factor 2 (Porf-2) on neural stem cells (NSCs) remain largely unknown. Here, we found that Porf-2 inhibits the activity of ras-related C3 botulinum toxin substrate 1 (Rac1) protein in hippocampus-derived rat NSCs. Reduced Rac1 activity impaired the nuclear translocation of β-catenin, ultimately causing a repression of NSCs proliferation. Porf-2 knockdown enhanced NSCs proliferation but not in the presence of small molecule inhibitors of Rac1 or Wnt. At the same time, the repression of NSCs proliferation caused by Porf-2 overexpression was counteracted by small molecule activators of Rac1 or Wnt. By using a rat optic nerve crush model, we observed that Porf-2 knockdown enhanced the recovery of visual function. In particular, optic nerve injury in rats led to increased Wnt family member 3a (Wnt3a) protein expression, which we found responsible for enhancing Porf-2 knockdown-induced NSCs proliferation. These findings suggest that Porf-2 exerts its inhibitory effect on NSCs proliferation via Rac1-Wnt/β-catenin pathway. Porf-2 may therefore represent and interesting target for optic nerve injury recovery and therapy.