Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans

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Project Summary Synaptic development is a highly conserved process that underlies the functional connectivity of the nervous system. Deficits in synaptic development are associated with multiple neurological disorders, like autism spectrum disorders, intellectual disabilities, epilepsy, and schizophrenia. Therefore, restoration of healthy synapse development in cases of neurodevelopmental disorders represents one goal for developing better treatments. However, the lack of molecular targets to achieve this goal presents a significant barrier to the development of new therapies. Identifying the signaling pathways that promote or restore synapse development will reveal new mechanisms for modulating neuronal circuit development and function. The overall goal for the proposed research is to uncover how a series of small GTPases coordinate synapse development at the Caenorhabditis elegans neuromuscular junction. The central hypothesis is that PXF-1, a Rap guanine nucleotide exchange factor, promotes synapse development through the sequential activation of Rap, Ras, and Rac GTPases to sustain perisynaptic actin filaments during neuromuscular development. To identify the molecular mechanisms that govern the putative GTPase signaling cascade, we will use genetics and cell biology to identify the guanine nucleotide exchange factors and GTPase activating proteins that modulate each GTPase in the pathway. We will use fluorescent biosensors and genetic engineering to elucidate the molecular mechanisms through which Rap, Ras, and Rac signaling pathways interact with one another. The proposed research is innovative because it uses the powerful model system of Caenorhabditis elegans to study how GTPase networks function as molecular switches to control synapse development and motor circuit function. The development and use of new molecular tools to observe and modulate signal transduction in vivo will provide additional innovations for cellular and molecular neuroscience. The studies proposed in this application are significant because they will reveal how small G protein signaling networks promote synapse development and how modulation of these GTPase signaling modules can mitigate neuronal circuit dysfunctions.