1. Neuroscience

Gab1 mediates PDGF signaling and is essential to oligodendrocyte differentiation and CNS myelination

  1. Liang Zhou
  2. Chong-Yu Shao
  3. Ya-Jun Xie
  4. Na Wang
  5. Si-Min Xu
  6. Ben-Yan Luo
  7. Zhi-Ying Wu
  8. Yue Hai Ke
  9. Mengsheng Qiu
  10. Ying Shen  Is a corresponding author
  1. Zhejiang University School of Medicine, China
  2. Zhejiang University City College, China
  3. Hangzhou Normal University, China
https://doi.org/10.7554/eLife.52056
Share this article
Cite this article
  1. Liang Zhou
  2. Chong-Yu Shao
  3. Ya-Jun Xie
  4. Na Wang
  5. Si-Min Xu
  6. Ben-Yan Luo
  7. Zhi-Ying Wu
  8. Yue Hai Ke
  9. Mengsheng Qiu
  10. Ying Shen
(2020)
Gab1 mediates PDGF signaling and is essential to oligodendrocyte differentiation and CNS myelination
eLife 9:e52056.
https://doi.org/10.7554/eLife.52056
  2. Download BibTeX
  3. Download .RIS

Abstract

Oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons in the central nervous system (CNS). Platelet-derived growth factor (PDGF) is critical for steady-state number and differentiation of oligodendrocyte precursor cells (OPCs), but its downstream targets are unclear. Here, we show for the first time that Gab1, an adaptor protein of receptor tyrosine kinase, is specifically expressed in OL lineage cells and is an essential effector of PDGF signaling in OPCs in mice. Gab1 is down-regulated by PDGF stimulation and up-regulated during OPC differentiation. Conditional deletions of Gab1 in OLs cause CNS hypomyelination by affecting OPC differentiation. Moreover, Gab1 binds to downstream GSK3β and regulated its activity, and thereby affects the nuclear accumulation of β-catenin and the expression of a number of transcription factors critical to myelination. Our work uncovers a novel downstream target of PDGF signaling, which is essential to OPC differentiation and CNS myelination.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Liang Zhou

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Chong-Yu Shao

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Ya-Jun Xie

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Na Wang

    School of Medicine, Zhejiang University City College, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Si-Min Xu

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Ben-Yan Luo

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Zhi-Ying Wu

    Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Yue Hai Ke

    Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Mengsheng Qiu

    Institute of Life Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Ying Shen

    Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
    For correspondence
    yshen@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7034-5328

Funding

Ministry of Science and Technology of the People's Republic of China (2017YFA0104200)

  • Ying Shen

National Natural Science Foundation of China (31571051)

  • Liang Zhou

National Natural Science Foundation of China (81625006)

  • Ying Shen

National Natural Science Foundation of China (31820103005)

  • Ying Shen

Natural Science Foundation of Zhejiang Province (Z15C090001)

  • Ying Shen

Natural Science Foundation of Zhejiang Province (LQ17C090001)

  • Na Wang

Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT31038)

  • Ying Shen

Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT31041)

  • Ying Shen

Chinese Ministry of Education Project 111 Program (B13026)

  • Ying Shen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Moses V Chao, New York University Langone Medical Center, United States

Ethics

Animal experimentation: All of the animals were handled according to approved protocol (ZJU20160019) of the Animal Experimentation Ethics Committee of Zhejiang University.

Version history

  1. Received: September 20, 2019
  2. Accepted: January 14, 2020
  3. Accepted Manuscript published: January 16, 2020 (version 1)
  4. Version of Record published: January 27, 2020 (version 2)

Copyright

© 2020, Zhou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,867
    views
  • 321
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Liang Zhou
  2. Chong-Yu Shao
  3. Ya-Jun Xie
  4. Na Wang
  5. Si-Min Xu
  6. Ben-Yan Luo
  7. Zhi-Ying Wu
  8. Yue Hai Ke
  9. Mengsheng Qiu
  10. Ying Shen
(2020)
Gab1 mediates PDGF signaling and is essential to oligodendrocyte differentiation and CNS myelination
eLife 9:e52056.
https://doi.org/10.7554/eLife.52056

Share this article

https://doi.org/10.7554/eLife.52056

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling

    Katarzyna Marta Zoltowska, Utpal Das ... Lucía Chávez-Gutiérrez
    Research Article

    Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.

    1. Computational and Systems Biology
    2. Neuroscience

    Myelin dystrophy impairs signal transmission and working memory in a multiscale model of the aging prefrontal cortex

    Sara Ibañez, Nilapratim Sengupta ... Christina M Weaver
    Research Article

    Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

    1. Neuroscience

    Prediction error determines how memories are organized in the brain

    Nicholas GW Kennedy, Jessica C Lee ... Nathan M Holmes
    Research Article

    How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.