Functional Characterization of Na+/Ca2+ Exchangers in Caenorhabditis elegans

Description

<p> Na⁺/Ca²⁺ exchangers are low affinity/high capacity transporters that mediate Ca²⁺ extrusion by coupling Ca²⁺ efflux to the influx of Na⁺ ions. Their primary function is to maintain Ca²⁺ homeostasis in cells of all organisms and they play a particularly important role in excitable cells that experience transient Ca²⁺ 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⁺/Ca²⁺ 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&rsquo;s Disease, Parkinson&rsquo;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⁺/Ca²⁺ exchangers in the invertebrate model organism <i>Caenorhabditis elegans </i>. There are ten identified Na⁺/Ca²⁺ 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⁺/Ca²⁺ 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⁺/Ca²⁺ exchanger genes in egg-laying, lipid storage and longevity, suggesting a role in diverse biological functions for Na⁺/Ca²⁺ exchangers in <i>C. elegans</i>. The function of an NCLX type Na⁺/Ca²⁺ 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⁺/Ca²⁺ exchanger, similar to NCLX, which is its homolog in humans.</p>

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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