Wnt signaling promotes regeneration in the retina of adult mammals
Wnt signaling promotes regeneration in the retina of adult mammals
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DOI：
10.1523/jneurosci.4193-06.2007
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发表时间：
2007-04-11
影响因子：
5.3
通讯作者：
Takahashi, Masayo
中科院分区：
文献类型：
--
作者：
Osakada, Fumitaka;Ooto, Sotaro;Takahashi, Masayo
哺乳动物中枢神经系统的再生受到严重限制。与小鸡不同，目前的模型认为视网膜神经元永远不会再生。先前我们已经证明，在成年哺乳动物的视网膜中，在体内急性神经毒性损伤后，Muller胶质细胞去分化并产生包括光感受器在内的视网膜细胞。然而，新生成的视网膜神经元的数量非常有限。在这里，我们证明了WNT(无翼型MMTV整合位点家族)/β-catenin信号促进了Muller神经胶质细胞来源的视网膜前体细胞的增殖和损伤后或变性过程中的神经再生。WNT3a治疗使光感受器受损的视网膜中去分化的穆勒胶质细胞的增殖增加20倍。补充维甲酸或丙戊酸可诱导这些细胞分化为CRX(视锥细胞同源盒)阳性和视紫红质阳性感受器。值得注意的是，损伤诱导了β-连环蛋白的核积聚，细胞周期蛋白D1上调，以及Wnt/β-连环蛋白报告活性。糖原合成酶-3β抑制剂激活Wnt信号可促进视网膜再生，反之，抑制该信号则抑制再生。这种由Wnt3a介导的视网膜细胞再生也发生在RD小鼠身上，RD小鼠是视网膜退化的模型。这些结果为Wnt/β-catenin信号在成年哺乳动物中枢神经系统再生中的作用提供了证据。
Regeneration in the mammalian CNS is severely limited. Unlike in the chick, current models hold that retinal neurons are never regenerated. Previously we demonstrated that, in the adult mammalian retina, Muller glia dedifferentiate and produce retinal cells, including photoreceptors, after acute neurotoxic injury in vivo. However, the number of newly generated retinal neurons is very limited. Here we demonstrate that Wnt (wingless-type MMTV integration site family)/beta-catenin signaling promotes proliferation of Muller glia-derived retinal progenitors and neural regeneration after damage or during degeneration. Wnt3a treatment increases proliferation of dedifferentiated Muller glia > 20-fold in the photoreceptor-damaged retina. Supplementation with retinoic acid or valproic acid induces differentiation of these cells primarily into Crx ( cone rod homeobox)- positive and rhodopsin-positive photoreceptors. Notably, injury induces nuclear accumulation of beta-catenin, cyclin D1 upregulation, and Wnt/beta-catenin reporter activity. Activation of Wnt signaling by glycogen synthase kinase-3 beta inhibitors promotes retinal regeneration, and, conversely, inhibition of the signaling attenuates regeneration. This Wnt3a-mediated regeneration of retinal cells also occurs in rd mice, a model of retinal degeneration. These results provide evidence that Wnt/beta-catenin signaling contributes to CNS regeneration in the adult mammal.