Identifying human 21st chromosome orthologs required for neuronal function in Caenorhabditis elegans




Nordquist, Sarah Katrina

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Down syndrome, caused by trisomy of the 21st chromosome, leads to lifelong cognitive impairment, characterized by alterations to neural cells and circuits, brain tissue, and behavior. Efforts to understand this disorder first require an understanding of the genes encoded on the 21st chromosome. The small roundworm, Caenorhabditis elegans, is an excellent model to uncover the in vivo function of human 21st chromosome orthologs. The first chapter of my dissertation provides background on Down syndrome—how it is thought to arise, the phenotypes it causes within the nervous system, which genes and pathways may underlie these phenotypes, and a brief survey of the established mouse models used to interrogate the disorder. I conclude by arguing that the more tractable model organism, C. elegans, can be used to complement research with rodents and that worm is a particularly fruitful system for initial gene characterization. In my next chapter, I discuss two systematic screens I performed on human 21st chromosome orthologs in worm: the first, a behavioral screen to identify genes broadly affecting nervous system function; the second, a pharmacological screen to identify genes involved in synaptic signaling. In these two screens, I identified a handful of candidate genes, several of which had not previously been linked to the nervous system in any animal. In Chapter 3, I discuss one of these novel candidate genes, mtq-2, that emerged from my screen. I provide a fuller characterization of it and show that it is required for normal nervous system function, normal excitatory neurotransmission, and that it functions, specifically, in cholinergic neurons to mediate its effects. I also discuss the potential genetic pathways in which mtq-2 may work to control synaptic vesicle release in excitatory motor neurons. Here, I present evidence that suggests mtq-2 may function upstream of or in conjunction with at least one Gα signaling protein, GαO. I conclude by sharing preliminary results on overexpression of mtq-2 and suggest future directions for inquiry.



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