Sequential phosphorylation of NDEL1 by the DYRK2-GSK3β complex is critical for neuronal morphogenesis
- Pohang University of Science and Technology, Republic of Korea
- Korea Brain Research Institute, Republic of Korea
- 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
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.
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.
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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