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.

Ethics

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

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

  • 1,984
    views
  • 333
    downloads
  • 18
    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. Neuroscience

    Reduced discrimination between signals of danger and safety but not overgeneralization is linked to exposure to childhood adversity in healthy adults

    Maren Klingelhöfer-Jens, Katharina Hutterer ... Tina B Lonsdorf
    Research Article

    Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of ‘exposure.’ Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and cognitive processes and ultimately behavior. 1402 healthy participants underwent a fear conditioning paradigm (acquisition training, generalization), while acquiring skin conductance responses (SCRs) and ratings (arousal, valence, and contingency). Childhood adversity was operationalized as (1) dichotomization, and following (2) the specificity model, (3) the cumulative risk model, and (4) the dimensional model. Individuals exposed to childhood adversity showed blunted physiological reactivity in SCRs, but not ratings, and reduced CS+/CS- discrimination during both phases, mainly driven by attenuated CS+ responding. The latter was evident across different operationalizations of ‘exposure’ following the different theories. None of the theories tested showed clear explanatory superiority. Notably, a remarkably different pattern of increased responding to the CS- is reported in the literature for anxiety patients, suggesting that individuals exposed to childhood adversity may represent a specific sub-sample. We highlight that theories linking childhood adversity to (vulnerability to) psychopathology need refinement.

    1. Neuroscience

    Robust variability of grid cell properties within individual grid modules enhances encoding of local space

    William T Redman, Santiago Acosta-Mendoza ... Michael J Goard
    Research Article

    Although grid cells are one of the most well-studied functional classes of neurons in the mammalian brain, whether there is a single orientation and spacing value per grid module has not been carefully tested. We analyze a recent large-scale recording of medial entorhinal cortex to characterize the presence and degree of heterogeneity of grid properties within individual modules. We find evidence for small, but robust, variability and hypothesize that this property of the grid code could enhance the encoding of local spatial information. Performing analysis on synthetic populations of grid cells, where we have complete control over the amount heterogeneity in grid properties, we demonstrate that grid property variability of a similar magnitude to the analyzed data leads to significantly decreased decoding error. This holds even when restricted to activity from a single module. Our results highlight how the heterogeneity of the neural response properties may benefit coding and opens new directions for theoretical and experimental analysis of grid cells.

    1. Genetics and Genomics
    2. Neuroscience

    Impact of liver-specific survival motor neuron (SMN) depletion on central nervous system and peripheral tissue pathology

    Monique Marylin Alves de Almeida, Yves De Repentigny ... Rashmi Kothary
    Research Article

    Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. While traditionally viewed as a motor neuron disorder, there is involvement of various peripheral organs in SMA. Notably, fatty liver has been observed in SMA mouse models and SMA patients. Nevertheless, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this, we developed a mouse model with a liver-specific depletion of SMN by utilizing an Alb-Cre transgene together with one Smn2B allele and one Smn1 exon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), when the severe model of SMA, the Smn2B/- mice, exhibit many symptoms of the disease. The liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the Smn2B/- mouse at P19. However, mild liver steatosis was observed, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of Smn2B/-mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producingα-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1). These changes were transient, as mice at P60 exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA.