Identifying key genetic regulators of nervous system health: Insights from models of neuronal development and aging

The nervous system is one of the most fascinating aspects of biology. Investigation into the innerworkings of the nervous system has proven challenging due to the general difficulty of accessibility, vast swaths of biological diversity, and the general complexity of the entire system. In this dissertation, Drosophila melanogaster are highlighted as a model to better understand key genetic regulators of nervous system development and aging. Firstly, the integration of multiple large data sets from distinct studies allowed the identification of highly conserved genes involved in aging of the central nervous system in both humans and Drosophila. The validation of previously identified aging associated genes indicate the analysis presented here uncovered 22 novel aging associated genes. The genes uncovered in this manuscript may underly key aging pathways within these two species and highlight Drosophila are an ideal model to study the genetics underlying the aging central nervous system. A form of genetic regulation conserved between humans and Drosophila are micro-RNA (miRNA). Within Drosophila, Several highly human conserved micro-RNA (miRNA) regulate development of the peripheral neuromuscular junction (NMJ). Here we provide the first evidence that several miRNAs are required within glial tissue to regulate synaptogenesis of the Drosophila peripheral nervous system. We provide evidence for the first time that miR-14 is required for normal synaptic development and physiology. Loss of glial specific miR-14 results in abnormal F-actin formation at the neuronal level, likely through its predicted target Sema2b. Lastly, we show that a neuronal-illness associated miRNA, miR-92, is required in glia for appropriate development of synaptic boutons and synaptic physiology. Loss of glial specific miR-92 results in overactivation of its target Vha55, and increased permeability through the blood-brain barrier equivalent, subperineurial glia within these flies. Further, dysregulation of miR-92 and its target Vha55 result in increased immature synaptic connections, demonstrating miR-92 regulates mechanisms important for synaptogenesis. This suggests a potential mechanism may be conserved between humans and Drosophila wherein miR-92 regulates synaptogenesis through Vha55-dependent development of the blood-brain barrier. Overall, Drosophila melanogaster provide an ideal model to uncover key genetic pathways involved within the developing and aging nervous system