Defining the function of a novel insulin-like growth factor binding protein in CNS development and function

PROJECT SUMMARY/ABSTRACT Across the animal kingdom, specialized neurosecretory cells coordinate endocrine and central nervous system signals to construct neural circuits and maintain homeostasis. Insulin/insulin-like growth factors (IGFs) are key secreted neuropeptides whose signaling activities are strictly regulated by IGF-binding proteins (IGFBPs). Despite misregulated insulin/IGF signaling (IIS) being linked to the pathogenesis of neurodevelopmental disorders, the cellular and molecular mechanisms by which IGFBPs precisely tune IGF activity in the brain to sculpt neural circuits and modulate behavioral outputs are largely undefined. The Drosophila system provides an appealing model to address these questions given only two IGFBPs are encoded in the fly genome, Imp-L2 and Crimpy. Our lab discovered Crimpy and defined its role in facilitating TGFβ signaling at the peripheral neuromuscular junction, but its roles in the central brain and IGF regulation are completely unexplored. Our preliminary data suggest that Crimpy is required for axon morphogenesis and circuit formation of the mushroom body, the fly learning and memory center. We also demonstrated that Crimpy is required to promote wild-type sleep behavior. Notably, Crimpy’s cellular requirements for axon morphogenesis and sleep regulation were mapped to a cluster of 14 neurosecretory cells at the brain midline, termed insulin producing cells (IPCs), which produce and secrete insulin-like peptides/IGFs. Based on these results, we hypothesize that Crimpy tunes IGF signaling from IPCs to promote proper central brain circuit development and function. Through the use of innovative genetic schemes, immunocytochemistry, as well as behavioral and electrophysiological analyses, this proposal seeks to: 1) establish roles for Crimpy in IPCs for central brain morphogenesis and circuit formation, 2) assess Crimpy’s function in IPCs to promote wakefulness, and 3) define Crimpy’s regulatory actions on IGF activity/IIS. These studies will provide novel mechanistic insight into the regulatory mechanisms governing IGF activity to fill fundamental gaps in our understanding of IIS in constructing neural circuits and modulating behavior. In addition, these proposed goals and approaches will provide exceptional training opportunities to strengthen my technical and professional skills, and prepare me for independence as I advance in my scientific career.