Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex
Open accessAbstract
The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases.
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SRGAP2A and SYNGAP1 regulate small GTPases, which control synaptic function and morphology.
“Our data also suggest more direct effects through their regulation of small GTPases, which are known to control synaptic function and morphology.55,56”
From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [56]
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“55,56 The GAP activity of SYNGAP1 was recently shown to be dispensable for synaptic plasticity and learning in adult mice.”
Background
- Authors
- Um, K., Niu, S., Duman, J. G., Cheng, J. X., Tu, Y.-K., Schwechter, B., Liu, F., Hiles, L., Narayanan, A. S., Ash, R. T., Mulherkar, S., Alpadi, K., Smirnakis, S. M., & Tolias, K. F.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Tolias, Kimberley F.
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 29
- Issue
- 6
- Pages
- 701-715
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC4111230
- OpenAlex
- W2003944475
- Cited by
- 81
- References
- 54
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 12 · 2022: 2 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 6 · 2017: 9 · 2016: 14 · 2015: 5 · 2014: 1
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K01MH086119, K01MH089112)
- National Institute of Diabetes and Digestive and Kidney Diseases (R43DK131680)
- National Institute of Neurological Disorders and Stroke (R01NS062829)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- Rac1, Tiam1, BCR, dendritic spine remodeling, EphB receptors, synaptogenesis, small GTPase regulation, actin cytoskeleton remodeling, receptor internalization
- MeSH terms
- T-Lymphoma Invasion and Metastasis-inducing Protein 1, Animals, Electrophysiology, Endocytosis, Immunoenzyme Techniques, Synapses, Blotting, Western, Signal Transduction, Neurites, Mice, Knockout, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rac1 GTP-Binding Protein, RNA, Small Interfering, Receptors, Eph Family, Immunoprecipitation, Dendritic Spines, Mice, Proto-Oncogene Proteins c-bcr
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