Deubiquitinase USP9X controls Wnt signaling for CNS vascular formation and barrier maintenance
Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt-signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific Usp9x knockout mice exhibit reduced Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we identified β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological mouse models of impaired CNS vascular barrier function, including intracerebral hemorrhage and an oxygen-induced retinopathy, loss of Usp9x intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.
Authors
- Lei Shi (ORCID: https://orcid.org/0000-0003-1679-3618)
- Junhao Hu (ORCID: https://orcid.org/0000-0003-0699-1119)
- S Zhang
- Kunfu Ouyang (ORCID: https://orcid.org/0000-0003-0292-375X)
- Xiangjian Zheng (ORCID: https://orcid.org/0000-0001-6277-5168)
- Fei Gao (ORCID: https://orcid.org/0000-0002-1235-8005)
- Fangfang Wu (ORCID: https://orcid.org/0000-0002-1888-4516)
- Qing Liu (ORCID: https://orcid.org/0000-0001-7594-6798)
- Wei Liu (ORCID: https://orcid.org/0000-0002-9302-8170)
- Xiaohong Wang (ORCID: https://orcid.org/0000-0001-8628-243X)
- Jiyun Zhao (ORCID: https://orcid.org/0000-0001-5764-8009)
- Jiandong Hu (ORCID: https://orcid.org/0000-0003-2021-8886)
- Hong Ren (ORCID: https://orcid.org/0009-0005-6846-3479)
- Xudong Wu
- Yi Lei (ORCID: https://orcid.org/0000-0001-9596-3472)
- Yuming Liu
- Xiaoyang Qin (ORCID: https://orcid.org/0009-0004-4218-2452)
Institutions
- Chinese Academy of Sciences (CN)
- Tianjin Medical University General Hospital (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Peking University Shenzhen Hospital (CN)
- Institute of Zoology (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Developmental Cell
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1016/j.devcel.2025.01.009
- Citations
- 11
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Postdoctoral Research Foundation of China
- National Key Research and Development Program of China Stem Cell and Translational Research