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.
Highlights
RhoGTPases are molecular switches that orchestrate various signaling pathways and are best known for being master regulators of actin cytoskeleton polymerization and organization [1]
Expression of synaptic RhoGTPase regulatory proteins in neuronal development While previous studies have largely focused on a particular stage of synaptic development, we sought to determine how RhoGTPase regulators function throughout synaptic development by evaluating their contribution to both early development, when immature filopodia-like spine precursors form, and later synapse formation, when spines mature into a mushroomshaped morphology
We selected known synaptic RhoGTPase regulatory proteins, β-PIX, a Guanine Exchange Factors (GEFs) [5,23,24], and OLIGOPHRENIN-1, a GTPase-Activating Proteins (GAPs) protein that is mutated in non-syndromic mental retardation [15,18]
Summary
RhoGTPases are molecular switches that orchestrate various signaling pathways and are best known for being master regulators of actin cytoskeleton polymerization and organization [1]. 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 [2,3,4]. Further excitatory stimulation associated with long-term potentiation leads to Rac1-driven spine head expansion [6,11]. Through these mechanisms RhoGTPases impact learning and memory. Altered RhoGTPase signaling leads to abnormal spine morphology and synaptic development and appears to contribute to the pathology of neuronal disorders, such as Autism Spectrum Disorders and non-syndromic mental retardation, as well as neurodegenerative disorders, like Alzheimer’s disease (AD) [12,13,14,15,16]
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