Cullin 5 Regulates Cortical Layering by Modulating the Speed and Duration of Dab1-Dependent Neuronal Migration
Open accessAbstract
The multilayered mammalian neocortex develops by the coordinated immigration and differentiation of cells that are produced at distant sites. Correct layering requires an extracellular protein, Reelin (Reln), an intracellular signaling molecule, Disabled-1 (Dab1), and an E3 ubiquitin ligase, Cullin-5 (Cul5). Reln activates Dab1, which is then degraded by Cul5. Here we test whether Cul5 regulates neuron layering by affecting Dab1 stability or other mechanisms. We find that a stabilized mutant Dab1, which resists Cul5-dependent degradation, causes a similar phenotype to Cul5 deficiency. Moreover, Cul5 has no effect when Dab1 is absent. The effects of Cul5 and Dab1 are cell autonomous, and Cul5 regulates movement of early as well as late cortical neurons. Removing Cul5 increases the speed at which neurons migrate through the cortical plate by reducing the time spent stationary and increasing the speed of individual steps. These results show that Cul5 regulates neuron layering by stimulating Dab1 degradation and that Cul5 controls migration speed and stopping point, and they demonstrate the importance of negative feedback in signaling during cortical development.
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In Nova2−/− neurons, abnormal inclusion of exons 7b and 7c produces a more stable isoform that may antagonize the activity of DAB1Δ7bc.
“In Nova2−/− neurons, the abnormal inclusion of exons 7b and 7c produces a more stable isoform that may antagonize the activity of DAB1Δ7bc46,47.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [47]
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References 53 · Cited by 72
Research works printed but not linked: 1
- Morimura T Ogawa M Relative importance of the tyrosine phosphorylation sites of Disabled-1 to the transmission of Reelin signaling Brain Res 2009b 1304 26 37 19796633
- Authors
- Simó, S., Jossin, Y., & Cooper, J. A.
- Affiliations
- Fred Hutch Cancer Center (US)
- Corresponding author
- Cooper, Jonathan A.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-04-21
- Volume
- 30
- Issue
- 16
- Pages
- 5668-5676
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2866641
- OpenAlex
- W1995347424
- Cited by
- 72
- References
- 53
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 9 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 5 · 2012: 5
- FWCI
- 1.82
- 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)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
- Funders
- European Commission
- University of California, Los Angeles
- U.S. Public Health Service (CA41072)
- National Cancer Institute (R01-CA41072, R01CA041072)
- 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 › Developmental Biology and Gene Regulation
- Keywords
- CUL5, Dab1, reelin, neuronal migration, cortical lamination, neocortex development, protein degradation, E3 ubiquitin ligase, migration speed, cortical plate, negative feedback signaling
- MeSH terms
- Reelin Protein, Animals, Cell Line, Cell Movement, Cells, Cultured, Cerebral Cortex, Female, Nerve Tissue Proteins, Neurons, Pregnancy, Time Factors, Mice, Knockout, Cullin Proteins, Mice, Neurogenesis
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