<p> Na<sup>+</sup>/Ca<sup>2+</sup> exchangers are low affinity/high capacity transporters that mediate Ca<sup>2+</sup> extrusion by coupling Ca<sup>2+</sup> efflux to the influx of Na<sup>+</sup> ions. Their primary function is to maintain Ca<sup>2+</sup> homeostasis in cells of all organisms and they play a particularly important role in excitable cells that experience transient Ca<sup>2+</sup> fluxes. While their functions have been studied extensively in muscle cells, much is still unknown about their contributions to the nervous system. Data suggests that Na<sup>+</sup>/Ca<sup> 2+</sup> exchangers play a key role in neuronal processes such as memory formation, learning, oligodendrocyte differentiation and axon guidance. They are also implicated in pathologies such as Alzheimer’s Disease, Parkinson’s Disease, Multiple Sclerosis and Epilepsy. While they are implicated in critical neuronal processes, a clear understanding of their mechanism remains unknown. This dissertation examines the role of Na<sup>+</sup>/Ca<sup>2+</sup> exchangers in the invertebrate model organism <i>Caenorhabditis elegans </i>. There are ten identified Na<sup>+</sup>/Ca<sup>2+</sup> exchanger genes in <i>C. elegans</i> (labeled <i>ncx-1</i> to <i>ncx</i>-10). Data presented here is the first comprehensive description of their genetics and function in <i>C. elegans</i>. The expression pattern of all 10 Na<sup>+</sup>/Ca<sup>2+</sup> exchanger genes is described and their phylogeny is examined comparatively across humans and flies. Analysis of <i>ncx-2</i> and <i>ncx-8</i> mutants shows important roles for Na<sup>+</sup>/Ca<sup>2+</sup> exchanger genes in egg-laying, lipid storage and longevity, suggesting a role in diverse biological functions for Na<sup>+</sup>/Ca<sup>2+</sup> exchangers in <i>C. elegans</i>. The function of an NCLX type Na<sup>+</sup>/Ca<sup> 2+</sup> exchanger NCX-9 is also detailed comprehensively. Analysis of <i> ncx-9</i> mutants shows that NCX-9 is required for asymmetrical axon guidance choices made by the DD and VD GABAergic motor neuron circuit. Pathway analysis shows that NCX-9 regulates asymmetric circuit patterning through RAC-dependent UNC-6/Netrin signaling and LON-2/Glypican Heparan Sulfate signaling. <i> In vitro</i> analysis of NCX-9 physiology in HEK cells shows that NCX-9 is a mitochondrial Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, similar to NCLX, which is its homolog in humans.</p>
Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:10262140 |
Date | 08 April 2017 |
Creators | Sharma, Vishal |
Publisher | The George Washington University |
Source Sets | ProQuest.com |
Language | English |
Detected Language | English |
Type | thesis |
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