The Daam2–VHL–Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation
- Xiaoyun Ding1,
- Juyeon Jo2,
- Chih-Yen Wang2,
- Carlo D. Cristobal3,
- Zhongyuan Zuo4,
- Qi Ye2,
- Marvin Wirianto5,
- Aaron Lindeke-Myers2,
- Jong Min Choi6,
- Carrie A. Mohila7,8,
- Hiroshi Kawabe9,
- Sung Yun Jung6,
- Hugo J. Bellen1,4,10,11,
- Seung-Hee Yoo5 and
- Hyun Kyoung Lee1,2,3,11
- 1Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 3Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA;
- 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
- 5Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center, Houston, Texas 77030, USA;
- 6Center for Molecular Discovery, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 7Department of Pathology, Texas Children's Hospital, Houston, Texas 77030, USA;
- 8Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 9Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075 Goettingen, Germany;
- 10Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA;
- 11Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA
- Corresponding author: hyunkyol{at}bcm.edu
Abstract
Dysregulation of the ubiquitin–proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development. Using proteomic analysis of the Daam2–VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase Nedd4 is required for developmental myelination through stabilization of VHL via K63-linked ubiquitination. Furthermore, studies in mouse demyelination models and white matter lesions from patients with multiple sclerosis corroborate the function of this pathway during remyelination after WMI. Overall, these studies provide evidence that a signaling axis involving key UPS components contributes to oligodendrocyte development and repair and reveal a new role for Nedd4 in glial biology.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.338046.120.
- Received March 2, 2020.
- Accepted July 15, 2020.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
