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Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-019-14169-z Xianding Sun 1 , Yang Zhou 2 , Ruobin Zhang 1 , Zuqiang Wang 1 , Meng Xu 1 , Dali Zhang 1 , Junlan Huang 1 , Fengtao Luo 1 , Fangfang Li 1 , Zhenhong Ni 1 , Siru Zhou 1 , Hangang Chen 1 , Shuai Chen 1 , Liang Chen 1 , Xiaolan Du 1 , Bo Chen 1 , Haiyang Huang 1 , Peng Liu 1 , Liangjun Yin 3 , Juhui Qiu 4 , Di Chen 5 , Chuxia Deng 6, 7 , Yangli Xie 1 , Lingfei Luo 2 , Lin Chen 1
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-019-14169-z Xianding Sun 1 , Yang Zhou 2 , Ruobin Zhang 1 , Zuqiang Wang 1 , Meng Xu 1 , Dali Zhang 1 , Junlan Huang 1 , Fengtao Luo 1 , Fangfang Li 1 , Zhenhong Ni 1 , Siru Zhou 1 , Hangang Chen 1 , Shuai Chen 1 , Liang Chen 1 , Xiaolan Du 1 , Bo Chen 1 , Haiyang Huang 1 , Peng Liu 1 , Liangjun Yin 3 , Juhui Qiu 4 , Di Chen 5 , Chuxia Deng 6, 7 , Yangli Xie 1 , Lingfei Luo 2 , Lin Chen 1
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Congenital scoliosis (CS) is a complex genetic disorder characterized by vertebral malformations. The precise etiology of CS is not fully defined. Here, we identify that mutation in dual serine/threonine and tyrosine protein kinase (dstyk) lead to CS-like vertebral malformations in zebrafish. We demonstrate that the scoliosis in dstyk mutants is related to the wavy and malformed notochord sheath formation and abnormal axial skeleton segmentation due to dysregulated biogenesis of notochord vacuoles and notochord function. Further studies show that DSTYK is located in late endosomal/lysosomal compartments and is involved in the lysosome biogenesis in mammalian cells. Dstyk knockdown inhibits notochord vacuole and lysosome biogenesis through mTORC1-dependent repression of TFEB nuclear translocation. Inhibition of mTORC1 activity can rescue the defect in notochord vacuole biogenesis and scoliosis in dstyk mutants. Together, our findings reveal a key role of DSTYK in notochord vacuole biogenesis, notochord morphogenesis and spine development through mTORC1/TFEB pathway.
中文翻译：
Dstyk突变通过失调的mTORC1 / TFEB途径在斑马鱼中导致先天性脊柱侧凸样椎骨畸形。
先天性脊柱侧凸（CS）是一种复杂的遗传性疾病，其特征是椎骨畸形。CS的确切病因尚未完全定义。在这里，我们确定在双丝氨酸/苏氨酸和酪氨酸蛋白激酶（dstyk）中的突变导致斑马鱼中的CS样椎骨畸形。我们证明，dstyk突变体中的脊柱侧弯与脊索空泡的生物发生失调和脊索功能紊乱有关，波状和畸形的脊索鞘形成和异常的轴向骨架分割相关。进一步的研究表明，DSTYK位于内体/溶酶体晚期区室，并参与哺乳动物细胞中的溶酶体生物发生。Dstyk组合式通过mTORC1依赖性抑制TFEB核转运来抑制线粒体液泡和溶酶体生物发生。抑制mTORC1活性可以挽救dstyk突变体中脊索空泡生物发生和脊柱侧弯的缺陷。总之，我们的发现揭示了DSTYK在通过mTORC1 / TFEB途径的脊索空泡生物发生，脊索形态发生和脊柱发育中的关键作用。
更新日期：2020-01-24
中文翻译：
Dstyk突变通过失调的mTORC1 / TFEB途径在斑马鱼中导致先天性脊柱侧凸样椎骨畸形。
先天性脊柱侧凸（CS）是一种复杂的遗传性疾病，其特征是椎骨畸形。CS的确切病因尚未完全定义。在这里，我们确定在双丝氨酸/苏氨酸和酪氨酸蛋白激酶（dstyk）中的突变导致斑马鱼中的CS样椎骨畸形。我们证明，dstyk突变体中的脊柱侧弯与脊索空泡的生物发生失调和脊索功能紊乱有关，波状和畸形的脊索鞘形成和异常的轴向骨架分割相关。进一步的研究表明，DSTYK位于内体/溶酶体晚期区室，并参与哺乳动物细胞中的溶酶体生物发生。Dstyk组合式通过mTORC1依赖性抑制TFEB核转运来抑制线粒体液泡和溶酶体生物发生。抑制mTORC1活性可以挽救dstyk突变体中脊索空泡生物发生和脊柱侧弯的缺陷。总之，我们的发现揭示了DSTYK在通过mTORC1 / TFEB途径的脊索空泡生物发生，脊索形态发生和脊柱发育中的关键作用。
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