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Description
MicroRNAs are fundamental regulators of gene expression whose dysfunction has been linked to many cancers and other diseases. Although many individual microRNA-gene interactions have been studied, to fully understand the function of a microRNA we must uncover its underlying genetic regulatory networks, beginning with its upstream and downstream factors. For my thesis work I focused on the developing peripheral nervous system (PNS) of the ascidian Ciona intestinalis, and in particular the upstream and downstream factors regulating the microRNA miR-124, which I showed is expressed in the ascidian PNS and promotes sensory neuron formation. Through computational and experimental analysis of the canonical targets of miR-124, I found that miR-124 promotes neurogenesis by a feedback interaction with genes of the Notch signaling pathway. Using transgenic assays along with in situ hybridization I then demonstrated that miR-124 is activated downstream of a linear network of conserved proneural genes, which in turn are also regulated by Notch signaling. I then developed a mathematical model that explains the patterning of sensory neurons in the ascidian PNS. Using this model I showed that the regulatory network comprising miR-124, proneural genes and Notch signaling is sufficient for neuronal patterning in Ciona. Importantly, I demonstrated that miR-124 regulation of Notch signaling can be accurately incorporated into the Notch decay rate parameter of the model. Altogether, I have uncovered the core regulatory network by which miR-124 promotes neuron formation in the Ciona PNS, which should motivate future studies on this important microRNA in other animals.
