Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan.
Stem Cells Dev. 2024 Oct;33(19-20):540-550. doi: 10.1089/scd.2023.0247. Epub 2024 Aug 9.
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 , encoding Deltex E3 ubiquitin ligase 2, is expressed in ependymo-radial glial cells in the adult spinal cord. After spinal cord injury, the heterozygous 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, 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.
脊髓创伤可导致严重的、永久性残疾。哺乳动物的脊髓不能再生；相比之下，成年斑马鱼有这种再生能力，可完全恢复运动功能。了解斑马鱼神经再生的机制可能为内源性再生潜力提供有用信息，并有助于在人类中开发治疗策略。DELTEX 蛋白（DTXs）调节多种细胞过程。然而，它们在神经再生中的作用尚未被描述。我们发现，斑马鱼 编码 Deltex E3 泛素连接酶 2，在成年脊髓的室管膜-放射状神经胶质细胞中表达。脊髓损伤后，杂合 突变鱼的运动功能比野生型对照鱼恢复得更快。突变鱼表现出更多的室管膜-放射状神经胶质细胞增殖和运动神经元形成。此外，下游 Notch 信号通路的 基因表达在 Dtx2 突变体中增加。Notch 信号通路失活通过显性负 Rbpj 消除了 Dtx2 缺乏引起的室管膜-放射状神经胶质细胞增殖增加。这些结果表明，由 Dtx2 缺乏引起的室管膜-放射状神经胶质细胞增殖是通过激活 Notch-Rbpj 信号来改善脊髓再生和运动功能恢复的。
