Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses

Abstract

Synapses mediate information flow between neurons and undergo plastic changes in response to experience, which is critical for learning and memory. Conversely, synaptic defects impair information processing and underlie many brain pathologies. Rho-family GTPases control synaptogenesis by transducing signals from extracellular stimuli to the cytoskeleton and nucleus. The Rho-GTPases Rac1 and Cdc42 promote synapse development and the growth of axons and dendrites, while RhoA antagonizes these processes. Despite its significance, many aspects of Rho-GTPase signaling remain relatively unknown. Rho-GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). Though the number of both GEFs and GAPs greatly exceeds that of Rho-GTPases, loss of even a single GEF or GAP often has profound effects on cognition and behavior. Here, we explore how the actions of specific GEFs and GAPs give rise to the precise spatiotemporal activation patterns of Rho-GTPases in neurons. We consider the effects of coupling GEFs and GAPs targeting the same Rho-GTPase and the modular pathways that connect specific cellular stimuli with a given Rho-GTPase via different GEFs. We discuss how the creation of sharp borders between Rho-GTPase activation zones is achieved by pairing a GEF for one Rho-GTPase with a GAP for another and the extensive crosstalk between different Rho-GTPases. Given the importance of synapses for cognition and the fundamental roles that Rho-GTPases play in regulating them, a detailed understanding of Rho-GTPase signaling is essential to the progress of neuroscience.

The Rac-GAP alpha2-chimaerin regulates hippocampal dendrite and spine morphogenesis

“…Furthermore, several disease-associated mutations have been identified in genes that regulate Rho-GTPase activity, underscoring that tight control of Rho-GTPase activity is imperative given their essential roles in diverse cellular processes (Penzes et al, 2011; Zoghbi and Bear, 2012). Although the molecular logic of GEF/GAP regulation of Rho-GTPases in response to synaptic activity is not well understood, the precise spatiotemporal activity of these modulatory proteins is likely to be highly choreographed and context-dependent (Duman et al, 2015). Thus, the cellular expression, subcellular localization, developmental regulation and protein-protein interactions of GEFs and GAPs are major factors that contribute to the spatiotemporal regulation and signaling specificity of Rho GTPases (Tolias et al, 2011).…”

Important roles of Vilse in dendritic architecture and synaptic plasticity

“…Rho GTPases play important roles in the morphogenesis of dendritic spines and synaptic plasticity by modulating the actin organization5678. RhoA is essential for stress fiber formation, whereas Rac and Cdc42 regulate the formation of lamellipodia and filopodia, respectively9.…”

Cellular mechanisms and signals that coordinate plasma membrane repair

“…Thus, GTPase activity flux controls the constriction of the contractile array responsible for wound closure. GTPase regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) have the ability to regulate spatiotemporal activity of GTPases [144], and regulation by these proteins has been proposed to provide the basis for GTPase flux during contractile array constriction [145]. …”

“…It seems likely that other GAP proteins are associated with each GTPase to prevent the constitutive activity of a GTPase within its own zone, thus regulating the temporal aspect of signaling. For example, the relationship between GEFs and GAPs themselves can determine whether GTPase activity will occur as a single long-lasting signal or as multiple transient spikes [144]. A final level of regulation adding to the complexity of GTPase signaling is their role in regulating phospholipases.…”