Date Published: January 23, 2017
Publisher: Public Library of Science
Author(s): Samuel Martin-Vilchez, Leanna Whitmore, Hannelore Asmussen, Jessica Zareno, Rick Horwitz, Karen Newell-Litwa, Stephane Gasman.
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.
RhoGTPases are molecular switches that orchestrate various signaling pathways and are best known for being master regulators of actin cytoskeleton polymerization and organization . Recently, they have emerged as crucial regulators of neuronal development, including dendritic arborization, growth cone development, axon guidance, and post-synaptic spine morphogenesis underlying excitatory neurotransmission [2–4]. During normal synaptic development, the small RhoGTPase, Rac1, promotes the formation of filopodia-like spine precursors [5–8] that subsequently mature through RhoA/ROCK-dependent myosin II activation into polarized mushroom-shape spines [9,10]. Further excitatory stimulation associated with long-term potentiation leads to Rac1-driven spine head expansion [6,11].
Our research demonstrates that unique combinations of Rho GTPase family members regulate distinct stages of synaptic development. Altered spine formation and maturation are increasingly implicated in neurodevelopmental disease pathology, whereas the maintenance of mature synaptic connections is lost in neurodegenerative disease pathology. In addition, regulatory pathways of the actin cytoskeleton are increasingly implicated in these neuronal disorders. Despite this association, how synaptic connections are temporally constructed and maintained has been unclear.