Reelin signals through apolipoprotein E receptor 2 and Cdc42 to increase growth cone motility and filopodia formation
Open accessAbstract
Lipoprotein receptor signaling regulates the positioning and differentiation of postmitotic neurons during development and modulates neuronal plasticity in the mature brain. Depending on the contextual situation, the lipoprotein receptor ligand Reelin can have opposing effects on cortical neurons. We show that Reelin increases growth cone motility and filopodia formation, and identify the underlying signaling cascade. Reelin activates the Rho GTPase Cdc42, known for its role in neuronal morphogenesis and directed migration, in an apolipoprotein E receptor 2-, Disabled-1-, and phosphatidylinositol 3-kinase-dependent manner. We demonstrate that neuronal vesicle trafficking, a Cdc42-controlled process, is increased after Reelin treatment and further provide evidence that the peptidergic VIP/PACAP38 system and Reelin can functionally interact to promote axonal branching. In conclusion, Reelin-induced activation of Cdc42 contributes to the regulation of the cytoskeleton of individual responsive neurons and converges with other signaling cascades to orchestrate Rho GTPase activity and promote neuronal development. Our data link the observation that defects in Rho GTPases and Reelin signaling are responsible for developmental defects leading to neurological and psychiatric disorders.
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Acute and chronic Reelin application enhances cortical neuritic outgrowth mobility and size, respectively, through an ApoER2/Dab1/PI3K pathway that activates Cdc42 and stimulates membrane delivery and growth cone extension.
“Acute and chronic Reelin application enhances cortical neuritic outgrowth mobility and size (respectively) through an ApoER2/Dab1/PI3K pathway, which activates the RhoGTPase Cdc42 and stimulates the delivery of membrane and extension of the growth cone (8) (Fig. 1D).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [8]
The ApoER2/Dab1/PI3K pathway can mediate the formation of axons by activating the RhoGTPase Cdc42.
“this ApoER2/Dab1/PI3K pathway can also mediate the formation of axons by activating the RhoGTPase Cdc42 (8).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [8]
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- Authors
- Leemhuis, J., Bouché, E., Frotscher, M., Henle, F., Hein, L., Herz, J., Meyer, D. K., Pichler, M., Roth, G., Schwan, C., & Bock, H. H.
- Affiliations
- University of Freiburg (DE)
- The University of Texas Southwestern Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-11-03
- Volume
- 30
- Issue
- 44
- Pages
- 14759-14772
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3523719
- OpenAlex
- W2017942806
- Cited by
- 80
- References
- 86
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 3 · 2013: 13 · 2012: 5
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Heart, Lung, and Blood Institute (R01HL063762, R37HL063762, P01HL020948)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- reelin, ApoER2, Cdc42, Rho GTPase signaling, growth cone motility, filopodia formation, axon branching, neuronal morphogenesis, neuronal migration, phosphatidylinositol 3-kinase, Disabled-1, cytoskeleton regulation
- MeSH terms
- Reelin Protein, Animals, Animals, Newborn, Cell Movement, Cells, Cultured, Cerebral Cortex, Humans, Nerve Tissue Proteins, Organ Culture Techniques, Pseudopodia, Serine Endopeptidases, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Receptors, Lipoprotein, Mice, Knockout, Phosphatidylinositol 3-Kinases, Growth Cones, cdc42 GTP-Binding Protein, LDL-Receptor Related Proteins, Mice, Rats, HEK293 Cells
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