Involvement of sonic hedgehog and notch signaling in regenerative neurogenesis in adult zebrafish optic tectum after stab injury
Involvement of sonic hedgehog and notch signaling in regenerative neurogenesis in adult zebrafish optic tectum after stab injury
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DOI：
10.1002/cne.24489
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发表时间：
2018-08
影响因子：
2.5
通讯作者：
Yuto Ueda;Y. Shimizu;Nobuyuki Shimizu;Tohru Ishitani;T. Ohshima
中科院分区：
文献类型：
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作者：
Yuto Ueda;Y. Shimizu;Nobuyuki Shimizu;Tohru Ishitani;T. Ohshima
与人类和其他哺乳动物不同，成年斑马鱼具有从中枢神经系统（CNS）损伤中恢复的上级能力。我们以前发现，放射状胶质细胞（RG）的增殖诱导反应在视顶盖刺伤和新的神经元产生RG刺伤后。然而，调节RG增殖和分化的分子机制尚不清楚。在本研究中，我们研究了Shh和Notch信号作为调节成年斑马鱼视顶盖再生的潜在机制。我们使用Shh报告鱼，并证实了典型的Shh信号被激活后，RG刺伤。此外，我们已经表明，Shh信号促进RG增殖，并抑制其分化为神经元刺伤后。相比之下，Notch信号在刺伤后下调，这通过Notch信号的靶基因her4和her6的表达水平的降低来指示。我们还发现，在刺伤后抑制Notch信号传导诱导更多的增殖RG，但抑制Notch信号传导抑制刺伤后RG新生神经元的产生。这些结果表明，高水平的Notch信号使RG保持静止，并且适当水平的Notch信号是RG产生新生神经元所必需的。在生理条件下，激活Shh信号或抑制Notch信号也可诱导RG增殖。在成年斑马鱼视顶盖中，经典Shh信号和Notch信号在生理和再生条件下RG的增殖和分化中发挥重要作用。
Unlike humans and other mammals, adult zebrafish have the superior capability to recover from central nervous system (CNS) injury. We previously found that proliferation of radial glia (RG) is induced in response to stab injury in optic tectum and that new neurons are generated from RG after stab injury. However, molecular mechanisms which regulate proliferation and differentiation of RG are not well known. In the present study, we investigated Shh and Notch signaling as potential mechanisms regulating regeneration in the optic tectum of adult zebrafish. We used Shh reporter fish and confirmed that canonical Shh signaling is activated specifically in RG after stab injury. Moreover, we have shown that Shh signaling promotes RG proliferation and suppresses their differentiation into neurons after stab injury. In contrast, Notch signaling was down‐regulated after stab injury, indicated by the decrease in the expression level of her4 and her6, a target gene of Notch signaling. We also found that inhibition of Notch signaling after stab injury induced more proliferative RG, but that inhibition of Notch signaling inhibited generation of newborn neurons from RG after stab injury. These results suggest that high level of Notch signaling keeps RG quiescent and that appropriate level of Notch signaling is required for generation of newborn neurons from RG. Under physiological condition, activation of Shh signaling or inhibition of Notch signaling also induced RG proliferation. In adult optic tectum of zebrafish, canonical Shh signaling and Notch signaling play important roles in proliferation and differentiation of RG in physiological and regenerative conditions.