Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition
Open accessAbstract
The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5–Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics.
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Mst3 phosphorylates RhoA on Ser26.
“Mammalian Ste20-like kinase 3 (Mst3) phosphorylates RhoA on Ser26 [60].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [60]
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Cites
Trekking across the Brain: The Journey of Neuronal Migration
Ayala, R., Shu, T., & Tsai, L.-H. (2007) · Cell · doi:10.1016/j.cell.2006.12.021 · Cited by 620 · see citing works
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Research works printed but not linked: 2
- Sidman RL, Rakic P (1973) Neuronal migration, with special reference to developing human brain: a review. Brain Res 62:1-35. CrossRef Medline
- Ye T, Fu AKY, Ip NY (2012) Cyclin-dependent kinase 5 in axon growth and regeneration. In: International review of neurobiology (Jeffrey LG, Ephraim FT, eds), pp 91-115. San Diego: Academic.
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RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
- Authors
- Tang, J., Ip, J. P. K., Ye, T., Ng, Y.-P., Yung, W.-H., Wu, Z., Fang, W., Fu, A. K. Y., & Ip, N. Y.
- Affiliations
- Hong Kong University of Science and Technology (HK)
- Chinese University of Hong Kong (HK)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-05-28
- Volume
- 34
- Issue
- 22
- Pages
- 7425-7436
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6795244
- OpenAlex
- W2032277135
- Cited by
- 68
- References
- 1
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 5 · 2014: 2
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion, cc-by)
- Funders
- University Grants Committee
- Hong Kong University of Science and Technology
- Innovation and Technology Fund
- Shenzhen Peacock Plan
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- MST3, cyclin-dependent kinase 5, RhoA, neuronal migration, radial migration, cortical lamination, actin cytoskeleton, microtubule cytoskeleton, neuronal morphogenesis, neocortex development, kinase regulation
- MeSH terms
- Hippo Kinases, Amino Acid Sequence, Animals, Animals, Newborn, Cell Movement, Cells, Cultured, Enzyme Activation, Female, Humans, Male, Mice, Inbred ICR, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein Serine-Threonine Kinases, Mice, Knockout, Neocortex, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Cyclin-Dependent Kinase 5, Mice, Rats, HEK293 Cells
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