Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway

Xianding Sun, Yang Zhou, Ruobin Zhang, Zuqiang Wang, Meng Xu, Dali Zhang, Junlan Huang, Fengtao Luo, Fangfang Li, Zhenhong Ni, Siru Zhou, Hangang Chen, Shuai Chen, Liang Chen, Xiaolan Du, Bo Chen, Haiyang Huang, Peng Liu, Liangjun Yin, Juhui Qiu, Di Chen, Chuxia Deng, Yangli Xie (), Lingfei Luo () and Lin Chen ()
Additional contact information
Xianding Sun: Army Medical University
Yang Zhou: Southwest University
Ruobin Zhang: Army Medical University
Zuqiang Wang: Army Medical University
Meng Xu: Army Medical University
Dali Zhang: Army Medical University
Junlan Huang: Army Medical University
Fengtao Luo: Army Medical University
Fangfang Li: Army Medical University
Zhenhong Ni: Army Medical University
Siru Zhou: Army Medical University
Hangang Chen: Army Medical University
Shuai Chen: Army Medical University
Liang Chen: Army Medical University
Xiaolan Du: Army Medical University
Bo Chen: Army Medical University
Haiyang Huang: Army Medical University
Peng Liu: Army Medical University
Liangjun Yin: Chongqing Medical University
Juhui Qiu: Chongqing University
Di Chen: Rush University Medical Center
Chuxia Deng: National Institutes of Health
Yangli Xie: Army Medical University
Lingfei Luo: Southwest University
Lin Chen: Army Medical University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-14169-z

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