Abstract
AbstractCongenital 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.
Funder
National Natural Science Foundation of China
National Key Research and Development Program of China
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference64 articles.
1. Weiss, H. R. & Moramarco, M. Congenital scoliosis (Mini-review). Curr. Pediatr. Rev. 12, 43–47 (2016).
2. Sparrow, D. B. et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell 149, 295–306 (2012).
3. Giampietro, P. F. et al. Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans. Ann. N. Y. Acad. Sci. 1151, 38–67 (2009).
4. Giampietro, P. F. et al. Clinical, genetic and environmental factors associated with congenital vertebral malformations. Mol. Syndromol. 4, 94–105 (2013).
5. Beauregard-Lacroix, E. et al. Retrospective analysis of congenital scoliosis: associated anomalies and genetic diagnoses. Spine 42, E841–E847 (2017).
Cited by
34 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献