PUBLICATION
EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis
- Authors
- Wang, L., Yang, X., Zhao, S., Zheng, P., Wen, W., Xu, K., Cheng, X., Li, Q., Khanshour, A.M., Koike, Y., Liu, J., Fan, X., Otomo, N., Chen, Z., Li, Y., Li, L., Xie, H., Zhu, P., Li, X., Niu, Y., Wang, S., Liu, S., Yuan, S., Terao, C., Li, Z., Chen, S., Zhao, X., Liu, P., Posey, J.E., Wu, Z., Qiu, G., DISCO study group (Deciphering Disorders Involving Scoliosis & COmorbidities), Ikegawa, S., Lupski, J.R., Rios, J.J., Wise, C.A., Zhang, J.T., Zhao, C., Wu, N.
- ID
- ZDB-PUB-250716-2
- Date
- 2025
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Zhao, Chengtian
- Keywords
- EPHA4, central pattern generators, genetics, genomics, human, idiopathic scoliosis, medicine, pathogenesis, zebrafish
- MeSH Terms
-
- Animals
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Locomotion*/genetics
- Mutation
- Humans
- Scoliosis*/genetics
- Scoliosis*/physiopathology
- Zebrafish/genetics
- Signal Transduction*
- Receptor, EphA4*/genetics
- Receptor, EphA4*/metabolism
- PubMed
- 40662934 Full text @ Elife
Citation
Wang, L., Yang, X., Zhao, S., Zheng, P., Wen, W., Xu, K., Cheng, X., Li, Q., Khanshour, A.M., Koike, Y., Liu, J., Fan, X., Otomo, N., Chen, Z., Li, Y., Li, L., Xie, H., Zhu, P., Li, X., Niu, Y., Wang, S., Liu, S., Yuan, S., Terao, C., Li, Z., Chen, S., Zhao, X., Liu, P., Posey, J.E., Wu, Z., Qiu, G., DISCO study group (Deciphering Disorders Involving Scoliosis & COmorbidities), Ikegawa, S., Lupski, J.R., Rios, J.J., Wise, C.A., Zhang, J.T., Zhao, C., Wu, N. (2025) EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis. eLIFE. 13:.
Abstract
Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the epha4a mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down efnb3b, the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in NGEF, a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping