The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation

Xiaoyun Ding, Juyeon Jo, Chih Yen Wang, Carlo D. Cristobal, Zhongyuan Zuo, Qi Ye, Marvin Wirianto, Aaron Lindeke-Myers, Jong Min Choi, Carrie A. Mohila, Hiroshi Kawabe, Sung Yun Jung, Hugo J. Bellen, Seung Hee Yoo, Hyun Kyoung Lee

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1177-1189
Number of pages13
JournalGenes and Development
Volume34
Issue number17-18
DOIs
Publication statusPublished - 2020 Sept 1

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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