Dtx2 Deficiency Induces Ependymo-Radial Glial Cell Proliferation and Improves Spinal Cord Motor Function Recovery.

Stem cells and development Pub Date : 2024-10-01 Epub Date: 2024-08-09 DOI:10.1089/scd.2023.0247
Hao-Yuan Chen, Yin-Cheng Huang, Tu-Hsueh Yeh, Chia-Wei Chang, Yang-Jin Shen, Yi-Chieh Chen, Mu-Qun Sun, Yi-Chuan Cheng
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Abstract

Traumatic injury to the spinal cord can lead to significant, permanent disability. Mammalian spinal cords are not capable of regeneration; in contrast, adult zebrafish are capable of such regeneration, fully recovering motor function. Understanding the mechanisms underlying zebrafish neuroregeneration may provide useful information regarding endogenous regenerative potential and aid in the development of therapeutic strategies in humans. DELTEX proteins (DTXs) regulate a variety of cellular processes. However, their role in neural regeneration has not been described. We found that zebrafish dtx2, encoding Deltex E3 ubiquitin ligase 2, is expressed in ependymo-radial glial cells in the adult spinal cord. After spinal cord injury, the heterozygous dtx2 mutant fish motor function recovered quicker than that of the wild-type controls. The mutant fish displayed increased ependymo-radial glial cell proliferation and augmented motor neuron formation. Moreover, her gene expression, downstream of Notch signaling, increased in Dtx2 mutants. Notch signaling inactivation by dominant-negative Rbpj abolished the increased ependymo-radial glia proliferation caused by Dtx2 deficiency. These results indicate that ependymo-radial glial proliferation is induced by Dtx2 deficiency by activating Notch-Rbpj signaling to improve spinal cord regeneration and motor function recovery.

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Dtx2 缺乏会诱导上皮神经胶质细胞增殖,并改善脊髓运动功能的恢复。
脊髓外伤可导致严重的永久性残疾。哺乳动物的脊髓不能再生;相反,成年斑马鱼却能再生,完全恢复运动功能。了解斑马鱼神经再生的内在机制可提供有关内源性再生潜能的有用信息,并有助于人类治疗策略的开发。DTX 可调节多种细胞过程。然而,它们在神经再生中的作用尚未得到描述。我们发现斑马鱼 dtx2(编码 Deltex E3 泛素连接酶 2)在成体脊髓上皮神经胶质细胞中表达。脊髓损伤后,杂合子dtx2突变体鱼的运动功能比野生型对照组恢复得更快。突变体鱼的上皮神经胶质细胞增殖增加,运动神经元形成增多。此外,在Dtx2突变体中,Notch信号下游基因的表达也有所增加。通过显性阴性的 Rbpj 使 Notch 信号失活,可以消除 Dtx2 缺乏引起的上皮神经节胶质细胞增殖。这些结果表明,Dtx2缺乏会诱导上皮神经胶质增殖,通过激活Notch-Rbpj信号改善脊髓再生和运动功能恢复。
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