title: Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex.
abstract: 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.
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Kyongmi
authors: K
authors: Um
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Sanyong
authors: S
authors: Niu
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Joseph G
authors: JG
authors: Duman
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Jinxuan X
authors: JX
authors: Cheng
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Yen-Kuei
authors: YK
authors: Tu
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Brandon
authors: B
authors: Schwechter
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Feng
authors: F
authors: Liu
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Laura
authors: L
authors: Hiles
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Anjana S
authors: AS
authors: Narayanan
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Ryan T
authors: RT
authors: Ash
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Shalaka
authors: S
authors: Mulherkar
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Kannan
authors: K
authors: Alpadi
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors: Stelios M
authors: SM
authors: Smirnakis
authors: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: tolias@bcm.edu.
authors: Kimberley F
authors: KF
authors: Tolias
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049229:Dendritic Spines / Q000502:physiology*; D004594:Electrophysiology; D004705:Endocytosis; D020690:GTPase-Activating Proteins / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D016501:Neurites / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D036081:Receptors, Eph Family / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C484145:Abr protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D036081:Receptors, Eph Family; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr; D020830:rac1 GTP-Binding Protein