Department of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing, 400715, China.
Nat Commun. 2020 Jan 24;11(1):479. doi: 10.1038/s41467-019-14169-z.
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.
先天性脊柱侧凸（CS）是一种以椎体畸形为特征的复杂遗传疾病。CS 的精确病因尚未完全确定。在这里，我们发现双重丝氨酸/苏氨酸和酪氨酸蛋白激酶（dstyk）的突变导致斑马鱼出现类似 CS 的椎体畸形。我们证明，dstyk 突变体的脊柱侧凸与波浪状和畸形的脊索鞘形成以及由于脊索空泡和脊索功能的生物发生失调导致的异常轴骨骼分段有关。进一步的研究表明，DSTYK 位于晚期内体/溶酶体隔室中，并参与哺乳动物细胞中的溶酶体生物发生。Dstyk 敲低通过 mTORC1 依赖性抑制 TFEB 核易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 突变体中脊索空泡生物发生和脊柱侧凸的缺陷。总之，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、脊索形态发生和脊柱发育中的关键作用。
