Sequential phosphorylation of NDEL1 by the DYRK2-GSK3β complex is critical for neuronal morphogenesis

  1. Youngsik Woo
  2. Soo Jeong Kim
  3. Bo Kyoung Suh
  4. Yongdo Kwak
  5. Hyun-Jin Jung
  6. Truong Thi My Nhung
  7. Dong Jin Mun
  8. Ji-Ho Hong
  9. Su-Jin Noh
  10. Seunghyun Kim
  11. Ahryoung Lee
  12. Seung Tae Baek
  13. Minh Dang Nguyen
  14. Youngshik Choe
  15. Sang Ki Park  Is a corresponding author
  1. Pohang University of Science and Technology, Republic of Korea
  2. Korea Brain Research Institute, Republic of Korea
  3. University of Calgary, Canada

Abstract

Neuronal morphogenesis requires multiple regulatory pathways to appropriately determine axonal and dendritic structures, thereby to enable the functional neural connectivity. Yet, however, the precise mechanisms and components that regulate neuronal morphogenesis are still largely unknown. Here, we newly identified the sequential phosphorylation of NDEL1 critical for neuronal morphogenesis through the human kinome screening and phospho-proteomics analysis of NDEL1 from mouse brain lysate. DYRK2 phosphorylates NDEL1 S336 to prime the phosphorylation of NDEL1 S332 by GSK3b. TARA, an interaction partner of NDEL1, scaffolds DYRK2 and GSK3b to form a tripartite complex and enhances NDEL1 S336/S332 phosphorylation. This dual phosphorylation increases the filamentous actin dynamics. Ultimately, the phosphorylation enhances both axonal and dendritic outgrowth and promotes their arborization. Together, our findings suggest the NDEL1 phosphorylation at S336/S332 by the TARA-DYRK2-GSK3b complex as a novel regulatory mechanism underlying neuronal morphogenesis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 5, and 6.

Article and author information

Author details

  1. Youngsik Woo

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  2. Soo Jeong Kim

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Bo Kyoung Suh

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Yongdo Kwak

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Hyun-Jin Jung

    Neural Development and Disease Department, Korea Brain Research Institute, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Truong Thi My Nhung

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Dong Jin Mun

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  8. Ji-Ho Hong

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Su-Jin Noh

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. Seunghyun Kim

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  11. Ahryoung Lee

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  12. Seung Tae Baek

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  13. Minh Dang Nguyen

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Youngshik Choe

    Neural Development and Disease Department, Korea Brain Research Institute, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  15. Sang Ki Park

    Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
    For correspondence
    skpark@postech.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1023-7864

Funding

National Research Foundation of Korea (2015M3C7A1030964)

  • Sang Ki Park

National Research Foundation of Korea (2017M3C7A1047875)

  • Sang Ki Park

National Research Foundation of Korea (2017R1A5A1015366)

  • Sang Ki Park

National Research Foundation of Korea (2017R1A2B2009031)

  • Sang Ki Park

Canadian Institutes of Health Research

  • Minh Dang Nguyen

Ministry of Science, ICT and Future Planning (19-BR-02-01)

  • Youngshik Choe

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

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Ethics

Animal experimentation: All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Pohang University of Science and Technology (POSTECH-2019-0024 and POSTECH-2019-0025). All experiments were carried out in accordance with the approved guidelines. All surgery was performed under ketamine/xylazine cocktail anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: August 5, 2019
  2. Accepted: December 8, 2019
  3. Accepted Manuscript published: December 9, 2019 (version 1)
  4. Version of Record published: December 23, 2019 (version 2)

Copyright

© 2019, Woo 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.

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  1. Youngsik Woo
  2. Soo Jeong Kim
  3. Bo Kyoung Suh
  4. Yongdo Kwak
  5. Hyun-Jin Jung
  6. Truong Thi My Nhung
  7. Dong Jin Mun
  8. Ji-Ho Hong
  9. Su-Jin Noh
  10. Seunghyun Kim
  11. Ahryoung Lee
  12. Seung Tae Baek
  13. Minh Dang Nguyen
  14. Youngshik Choe
  15. Sang Ki Park
(2019)
Sequential phosphorylation of NDEL1 by the DYRK2-GSK3β complex is critical for neuronal morphogenesis
eLife 8:e50850.
https://doi.org/10.7554/eLife.50850

Share this article

https://doi.org/10.7554/eLife.50850

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