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

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...

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Bibliographic Details
Published in:eLife 2019-12, Vol.8
Main Authors: Woo, Youngsik, Kim, Soo Jeong, Suh, Bo Kyoung, Kwak, Yongdo, Jung, Hyun-Jin, Nhung, Truong Thi My, Mun, Dong Jin, Hong, Ji-Ho, Noh, Su-Jin, Kim, Seunghyun, Lee, Ahryoung, Baek, Seung Tae, Nguyen, Minh Dang, Choe, Youngshik, Park, Sang Ki
Format: Article
Language:English
Subjects:
Actin
Animals
axon/dendrite outgrowth
Brain
Carrier Proteins - metabolism
Cell adhesion & migration
Developmental Biology
Dyrk Kinases
filamentous actin dynamics
Glycogen Synthase Kinase 3 beta - metabolism
Humans
Kinases
Library collections
Mice
Microfilament Proteins - metabolism
Morphogenesis
Morphology
Mutation
NDEL1 phosphorylation
Neural networks
neuronal arborization
neuronal morphogenesis
Neurons - cytology
Neuroscience
Peptides
Phosphorylation
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases - metabolism
Protein-Tyrosine Kinases - metabolism
Proteins
Proteome - analysis
Proteomics
Schizophrenia
TARA-DYRK2-GSK3β complex
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Summary: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 GSK3β. TARA, an interaction partner of NDEL1, scaffolds DYRK2 and GSK3β 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-GSK3β complex as a novel regulatory mechanism underlying neuronal morphogenesis.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.50850