Dstyk mutation leads to congenital scoliosis-like vertebral malformations in zebrafish via dysregulated mTORC1/TFEB pathway
| Autor: | Dali Zhang, Chu-Xia Deng, Meng Xu, Liangjun Yin, Peng Liu, Hangang Chen, Juhui Qiu, Yangli Xie, Fengtao Luo, Xiaolan Du, Lin Chen, Ruobin Zhang, Zhenhong Ni, Liang Chen, Xianding Sun, Zuqiang Wang, Di Chen, Fangfang Li, Shuai Chen, Junlan Huang, Bo Chen, Siru Zhou, Yang Zhou, Haiyang Huang, Lingfei Luo |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
General Physics and Astronomy mTORC1 Vacuole 0302 clinical medicine lcsh:Science Zebrafish Multidisciplinary biology Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Notochord morphogenesis Bone development Cell biology medicine.anatomical_structure Scoliosis Gene Knockdown Techniques Receptor-Interacting Protein Serine-Threonine Kinases embryonic structures Signal Transduction animal structures Science Active Transport Cell Nucleus Notochord Development Models Biological General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Lysosome medicine Animals Humans Disease model fungi General Chemistry Zebrafish Proteins biology.organism_classification Spine Disease Models Animal 030104 developmental biology Mutation Vacuoles TFEB lcsh:Q Lysosomes 030217 neurology & neurosurgery Biogenesis Transcription Factors |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Congenital scoliosis is a complex genetic disorder characterized by vertebral malformation. Here, the authors demonstrate that loss of dstyk leads to scoliosis in zebrafish due to dysregulated biogenesis of notochord vacuoles and that DSTYK is required for lysosome biogenesis through mTORC1 regulation. |
| Databáze: | OpenAIRE |
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