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

Dali Zhang,Haiyang Huang,Lingfei Luo,Yangli Xie,Fangfang Li,Chu‐Xia Deng ,Junlan Huang,Shuai Chen,Xiaolan Du,Zuqiang Wang,Yin Liang ,Yang Zhou,Fei Luo ,Meng Xu,Siru Zhou,Di Chen,Bin Chen ,Peng Liu,Liang Chen,Juhui Qiu,Hangang Chen,Zhenhong Ni,Ruobin Zhang,Xianding Sun

doi:10.1038/s41467-019-14169-z

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.

Highlights

Congenital scoliosis (CS) is a complex genetic disorder characterized by vertebral malformations
In this study, using ENU mutagenesis screening, we found a mutation in dstyk can lead to CS-like vertebral malformations in zebrafish
We provide further evidence suggesting that the vertebral defects in dstyk mutants are related to the wavy and malformed notochord sheath and abnormal axial skeleton segmentation resulting from defect biogenesis of notochord vacuole (Fig. 10a)

Summary

Introduction

Congenital scoliosis (CS) is a complex genetic disorder characterized by vertebral malformations. Inhibition of mTORC1 activity can rescue the defect in notochord vacuole biogenesis and scoliosis in dstyk mutants. Congenital scoliosis (CS) is characterized by the lateral curvature of the spine with a Cobb angle >10 degrees and has an estimated prevalence approximately 1 in 1000 live births It is mainly caused by defects in vertebral formation during embryogenesis[1,2]. The vertebral defects in dstyk mutants are caused by abnormal notochord development resulting from defects in biogenesis of notochord vacuoles. We reveal that dstyk mutation leads to defects in lysosome biogenesis and vacuole formation through repressing TFEB nuclear translocation via activating mTORC1. Inhibition of mTORC1 activity can partially rescue the defect in the biogenesis of notochord vacuole and scoliosis in dstyk mutants

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Results

Conclusion