Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex

Kyongmi Um, Sanyong Niu, Joseph G. Duman, Jinxuan X. Cheng, Yen Kuei Tu, Brandon Schwechter, Feng Liu, Laura Hiles, Anjana S. Narayanan, Ryan T. Ash, Shalaka Mulherkar, Kannan Alpadi, Stelios M. Smirnakis, Kimberley F. Tolias

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish
Pages (from-to)701-715
Number of pages15
JournalDevelopmental cell
Volume29
Issue number6
DOIs
StatePublished - Jun 23 2014

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    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. (2014). Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex. Developmental cell, 29(6), 701-715. https://doi.org/10.1016/j.devcel.2014.05.011