Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway
Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway
复制标题
Dstyk 突变通过 mTORC1/TFEB 通路失调导致斑马鱼先天性脊柱侧凸样椎体畸形
DOI：
10.1038/s41467-019-14169-z
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发表时间：
2020-01-24
影响因子：
16.6
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Sun, Xianding;Zhou, Yang;Chen, Lin
先天性脊柱侧凸是一种以脊柱畸形为特征的复杂遗传性疾病。CS的确切病因尚未完全确定。在这里，我们确定了双重丝氨酸/苏氨酸和酪氨酸蛋白激酶(DSTYK)突变导致斑马鱼脊椎CS样畸形。我们证明，DSTYK突变体的脊柱侧弯与脊索鞘的波状和畸形的形成以及由于脊索空泡和脊索功能的生物发生失调而导致的轴向骨骼分割异常有关。进一步的研究表明，DSTYK位于晚期的内小体/溶酶体内，参与哺乳动物细胞中溶酶体的生物发生。DSTYK基因敲除通过依赖mTORC1抑制TFEB核转位来抑制脊索空泡和溶酶体的生物发生。抑制mTORC1活性可以挽救DSTYK突变体脊索空泡生物发生和脊柱侧弯的缺陷。综上所述，我们的研究结果揭示了DSTYK通过mTORC1/TFEB途径在脊索空泡生物发生、脊索形态发生和脊椎发育中的关键作用。
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.