RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development

Abstract

Small RhoGTPases regulate changes in post-synaptic spine morphology and density that support learning and memory. They are also major targets of synaptic disorders, including Autism. Here we sought to determine whether upstream RhoGTPase regulators, including GEFs, GAPs, and GDIs, sculpt specific stages of synaptic development. The majority of examined molecules uniquely regulate either early spine precursor formation or later maturation. Specifically, an activator of actin polymerization, the Rac1 GEF β-PIX, drives spine precursor formation, whereas both FRABIN, a Cdc42 GEF, and OLIGOPHRENIN-1, a RhoA GAP, regulate spine precursor elongation. However, in later development, a novel Rac1 GAP, ARHGAP23, and RhoGDIs inactivate actomyosin dynamics to stabilize mature synapses. Our observations demonstrate that specific combinations of RhoGTPase regulatory proteins temporally balance RhoGTPase activity during post-synaptic spine development.

A Molecular Tension Sensor for N-Cadherin Reveals Distinct Forms of Mechanosensitive Adhesion Assembly in Adherens and Synaptic Junctions

“…RhoA initiates LTP, while Rac1 supports later LTP consolidation [77]. Notably, key regulators of RhoGTPases that preferentially affect each stage of synaptic development, including a variety of GEFs and GAPs as well RhoGDI, have been identified [78]. A major question for future work will be determine if these regulators are subject to mechanosensitive regulation.…”

Forecasting autism gene discovery with machine learning and genome-scale data

“…This suggests that these pathways represent noted and plausible but still under-appreciated molecular themes in our understanding of autism. The pathway that underwent the largest relative increase in enrichment from SFARI HC to forecASD is Rho GTPase signaling (OR=2.2, P=4.8×10 −5 ), which plays a critical role in cytoskeletal dynamics in neurodevelopment(24), including interactions with SHANK proteins and the formation and maturation of dendritic spines(25). As another example, although chromatin modification in general is a well-established theme in autism genetic risk, histone acetyltransferases showed relatively little representation in the SFARI HC list, but were significantly enriched in forecASD genes (OR=4.1, P=3.5×10 −9 ).…”

Glia Promote Synaptogenesis through an IQGAP PES-7 in C. elegans

“…elegans CDC-42, first described in 1993 (Chen et al, 1993), regulates many cellular behaviors, including cell polarity, invasion, and neuronal protrusion (Gotta et al, 2001;Dyer et al, 2010;Kay and Hunter, 2001;Qiu et al, 2000;Lohmer et al, 2016;Alan et al, 2013). In mammals, the homolog CDC42 also regulates dendritic spine formation and plasticity (Tashiro et al, 2000;Tolias et al, 2011;Hedrick et al, 2016;Martin-Vilchez et al, 2017;Murakoshi et al, 2011;Bijata et al, 2017). Recently, CDC42 was also found to be required for presynaptic development in Drosophila and mice (Imai et al, 2016;Rodal et al, 2008), indicating that its roles in presynaptic assembly are evolutionarily conserved.…”