2. Academic Validation
  3. RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination

RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination

  • Sci Adv. 2024 Feb 9;10(6):eadk3931. doi: 10.1126/sciadv.adk3931.
Yuwei Li 1 2,  Li Pear Wan 1 2 3,  Ning-Ning Song 4,  Yu-Qiang Ding 4 5,  Shuhua Zhao 6,  Jianqin Niu 7,  Bingyu Mao 1 8,  Nengyin Sheng 1 3 8,  Pengcheng Ma 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
  • 2 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650223, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
  • 4 Department of Laboratory Animal Science, Fudan University, Shanghai 200032, China.
  • 5 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
  • 6 First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
  • 7 Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China.
  • 8 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
PMID: 38324685 DOI: 10.1126/sciadv.adk3931
Abstract

Maldevelopment of oligodendroglia underlies neural developmental disorders such as leukodystrophy. Precise regulation of the activity of specific transcription factors (TFs) by various posttranslational modifications (PTMs) is required to ensure proper oligodendroglial development and myelination. However, the role of ubiquitination of these TFs during oligodendroglial development is yet unexplored. Here, we find that RNF220, a known leukodystrophy-related E3 ubiquitin ligase, is required for oligodendroglial development. RNF220 depletion in oligodendrocyte lineage cells impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, which consequently leads to learning and memory defects. Mechanistically, RNF220 targets Olig1/2 for K63-linked polyubiquitination and stabilization during oligodendroglial development. Furthermore, in a knock-in mouse model of leukodystrophy-related RNF220R365Q mutation, the ubiquitination and stabilization of Olig proteins are deregulated in oligodendroglial cells. This results in pathomimetic oligodendroglial developmental defects, impaired myelination, and abnormal behaviors. Together, our evidence provides an alternative insight into PTMs of oligodendroglial TFs and how this essential process may be implicated in the etiology of leukodystrophy.

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