Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development
Open accessAbstract
Many laminated regions of the mammalian brain develop by the migration of neuronal precursor cells, whose final positions are coordinated by signals from the secreted molecule Reelin. Early events in Reelin signaling have been identified, but the mechanism of signal down-regulation has been unclear. A possible source of negative feedback is the Reelin-induced degradation of the critical intracellular signaling component, Disabled-1 (Dab1). Here we show that degradation of Dab1 depends on Dab1 phosphorylation at specific tyrosine residues and on the E3 ubiquitin ligase component Cullin 5 (Cul5). Cul5 forms complexes with SOCS (suppressors of cytokine signaling) proteins, which bind to phosphorylated Dab1 and target it for degradation in tissue culture cells. Ablation of Cul5 in migrating neurons causes an accumulation of active Dab1 protein and a unique cortical layering defect, characterized by excess migration and buildup of neurons at the top of the cortical plate. The results implicate Cul5 and SOCS proteins in down-regulation of Dab1 in vivo and show that Cul5 plays an essential role in regulating neuron migrations during cortical development, possibly by opposing a promigratory effect of Dab1.
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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 [46]
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- Authors
- Feng, L., Allen, N. S., Simo, S., & Cooper, J. A.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- ORCID
- Cooper, Jonathan A.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-11-01
- Volume
- 21
- Issue
- 21
- Pages
- 2717-2730
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2045127
- OpenAlex
- W2113752611
- Cited by
- 148
- References
- 59
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 8 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 11 · 2015: 7 · 2014: 13 · 2013: 8 · 2012: 12
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Genes & Development (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R37CA041072, CA41072, R01CA041072)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007183)
- 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, Disabled-1, Dab1, Reelin signaling, neuronal migration, cortical development, cortical lamination, suppressor of cytokine signaling, E3 ubiquitin ligase, protein degradation, tyrosine phosphorylation, negative feedback, cortical plate
- MeSH terms
- Reelin Protein, Animals, Cell Movement, Cells, Cultured, Chlorocebus aethiops, Cerebral Cortex, Embryo, Mammalian, HeLa Cells, Humans, Mice, Transgenic, Models, Biological, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein Kinases, Protein Processing, Post-Translational, Serine Endopeptidases, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, COS Cells, Cullin Proteins, Adaptor Proteins, Signal Transducing, Suppressor of Cytokine Signaling Proteins, Mice
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