EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis
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.
Authors
- James R. Lupski (ORCID: https://orcid.org/0000-0001-9907-9246)
- Qing Li (ORCID: https://orcid.org/0009-0000-5172-5755)
- Jennifer E. Posey (ORCID: https://orcid.org/0000-0003-4814-6765)
- Chikashi C. Terao (ORCID: https://orcid.org/0000-0002-6452-4095)
- Shengru Wang (ORCID: https://orcid.org/0009-0004-3749-4267)
- Xiuli Zhao (ORCID: https://orcid.org/0000-0001-8238-6311)
- Shiro Ikegawa (ORCID: https://orcid.org/0000-0003-0316-2147)
- Panpan Zhu (ORCID: https://orcid.org/0000-0001-8966-9402)
- Shaoke Chen
- Pengfei Zheng (ORCID: https://orcid.org/0000-0002-8729-0850)
- Lianlei Wang
- Anas M. Khanshour
- Guixing Qiu (ORCID: https://orcid.org/0000-0002-4597-9350)
- Nan Wu (ORCID: https://orcid.org/0000-0002-9429-2889)
- Yoshinao Koike (ORCID: https://orcid.org/0000-0002-5431-5572)
- Nao Otomo (ORCID: https://orcid.org/0000-0002-8686-2722)
- Carol A. Wise (ORCID: https://orcid.org/0000-0002-6790-2194)
- Chengtian Zhao (ORCID: https://orcid.org/0000-0003-1236-914X)
- Yuchen Niu (ORCID: https://orcid.org/0000-0001-9443-0586)
- Haibo Xie (ORCID: https://orcid.org/0000-0002-1350-9557)
- Jonathan J. Rios (ORCID: https://orcid.org/0000-0002-0969-2184)
- Ziquan Li (ORCID: https://orcid.org/0000-0002-8412-9965)
- Pengfei Liu (ORCID: https://orcid.org/0000-0002-4177-709X)
- Sen Liu (ORCID: https://orcid.org/0000-0001-7880-3223)
- Lulu Li (ORCID: https://orcid.org/0000-0003-1721-1288)
- Kexin Xu (ORCID: https://orcid.org/0009-0008-7644-8174)
- Jian‐Guo Zhang (ORCID: https://orcid.org/0009-0003-0655-3810)
- Jun‐Jun Liu (ORCID: https://orcid.org/0000-0002-9745-8258)
- Yaqi Li (ORCID: https://orcid.org/0000-0002-6829-8208)
- Xiaoxin Li (ORCID: https://orcid.org/0000-0002-8645-4331)
- Suomao Yuan (ORCID: https://orcid.org/0000-0001-5218-0654)
- Sen Zhao (ORCID: https://orcid.org/0009-0007-1473-635X)
- Xinyu Yang (ORCID: https://orcid.org/0009-0002-6706-9857)
- Zhihong Wu (ORCID: https://orcid.org/0000-0002-1902-4198)
- Xin Fan (ORCID: https://orcid.org/0000-0003-0307-1675)
- Wen Wen (ORCID: https://orcid.org/0000-0003-4858-8037)
- Xi Cheng
- Zefu Chen
Institutions
- Academy of Medical Sciences (GB)
- Baylor College of Medicine (US)
- Capital Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Texas Scottish Rite Hospital for Children (US)
- Beijing Institute of Big Data Research (CN)
- Southwestern Medical Center (US)
- Guangxi Maternal and Child Health Hospital (CN)
- Texas Children's Hospital (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Qilu Hospital of Shandong University (CN)
- Baylor Genetics (US)
- Beijing Obstetrics and Gynecology Hospital (CN)
- Ocean University of China (CN)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- eLife
- Published
- 2025-06-30
- DOI
- https://doi.org/10.7554/elife.95324.3
- Citations
- 1
- Primary Topic
- Connective tissue disorders research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Chinese Academy of Medical Sciences Initiative for Innovative Medicine