Identifying the insulin-signaling targets that regulate synapse development

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Our nervous system needs to generate and maintain functional neuronal and neuron-muscle connections. Using C. elegans, a small animal model, we discovered that an attenuation of insulin signalling not only restores the morphology and function of the neuron-muscle connection (called neuromuscular junctions) in genetic mutants with defective neuromuscular junction developments, but also exerts strong protection in animal models for neurodegeneration. Intriguingly, both the developmental and neural protective role of insulin signalling involves secretion of insulin from the nervous system, and the activation of a signalling cascade in the muscle cells, and both roles strictly depend on the presence of a transcription factor called DAF-16 in muscles. Hence, identification of muscle-specific DAF-16 transcriptional targets becomes critical for an understanding and biomedical application of the developmental and protective roles of insulin signalling. ******The goal of our project is to identify the DAF-16 transcriptional targets. Specifically, we will first utilize the C. elegans model to identify genes whose expression is specifically activated or repressed by DAF-16 in muscle cells, and perform functional assay to identify those that are critical for animals to maintain robust neuromuscular junction morphology and function. Upon the identification of such targets, we will further examine their biomedical impact by examining whether they affect the neuromuscular junction phenotype and function in the C. elegans neurodegenerative models, and whether they have functional conservation using a human iPS cell-derived in vitro neuromuscular system. *****