Identifying the insulin-signaling targets that regulate synapse development

我们的神经系统需要产生和维持功能性神经元和神经元-肌肉连接。利用C. elegans，一种小动物模型，我们发现胰岛素信号传导的减弱不仅在具有缺陷的神经肌肉接头发育的遗传突变体中恢复神经元-肌肉连接（称为神经肌肉接头）的形态和功能，而且在神经变性的动物模型中发挥强有力的保护作用。有趣的是，胰岛素信号的发育和神经保护作用都涉及神经系统分泌胰岛素，以及肌肉细胞中信号级联的激活，这两种作用都严格依赖于肌肉中一种名为β-16的转录因子的存在。因此，识别肌肉特异性β-16转录靶点对于理解胰岛素信号传导的发育和保护作用及其生物医学应用至关重要。** 我们项目的目标是鉴定β-16转录靶标。具体来说，我们将首先利用C。elegans模型，以鉴定其表达在肌肉细胞中被β-16特异性激活或抑制的基因，并进行功能测定，以鉴定那些对动物维持稳健的神经肌肉接头形态和功能至关重要的基因。在鉴定出这些靶点后，我们将通过检测它们是否影响C. elegans神经退行性模型，以及它们是否具有使用人iPS细胞衍生的体外神经肌肉系统的功能保护。*****

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. *****