Dissertation/Thesis Abstract

Genetic Studies of Guanylate Cyclase Trafficking to the Sensory Cilium
by Martínez-Velázquez, Luis A., Ph.D., New York University, 2017, 175; 10618951
Abstract (Summary)

Animals detect a wide range of cues from the physical and chemical world that surrounds them through receptors on the surface of neurons specialized for sensation. Many sensory neurons share an anatomical architecture that segregates the signaling complexes involved in sensory transduction to the distal end of a dendrite and the machinery responsible for information outflow to an axon. At the distal end of the dendrite, multiple sensory neuron types of varied animals have co-opted the primary cilium, an organelle specialized for signal transduction, to organize the molecules involved in sensory transduction. In many sensory neurons, the sensory cilium is surrounded by a complex elaboration of cell’s plasma membrane that is adapted for the sensory modality of the neuron. Although the membranes of sensory cilia are densely packed with proteins involved in sensory transduction, sensory cilia lack the machinery required to synthesize proteins. Proteins must therefore be transported from their site of synthesis in the soma of sensory neurons to the cilium. The mechanisms underlying this trafficking process remain poorly understood.

My dissertation explores the question of how sensory transduction factors are trafficked to the sensory cilium through studies of molecular mechanisms involved in assembly of the sensory transduction apparatus in chemosensory BAG neurons of C. elegans. BAG neurons are ciliated, bipolar neurons that use an evolutionarily conserved signal transduction pathway involving cyclic nucleotide-gated (CNG) channels and a receptor-type guanylate cyclase (rGC) to detect the respiratory gas carbon dioxide (CO2). Previous studies showed that nematodes avoid CO2, and that this behavior relies on the TAX-4/TAX-2 CNG channel subunits and the BAG-specific rGC GCY-9. In Chapter Two of this dissertation, I discuss experimental evidence that suggests that GCY-9, a receptor-type guanylate cyclase, is the likely receptor for CO 2. Furthermore, I demonstrate that like many other chemosensory receptors of animals, GCY-9 localizes to the sensory cilium of BAG sensory neurons.

In Chapter Three of my thesis, I describe how I used BAG sensory neurons as a model to study molecular mechanisms involved in the traffic of rGCs to the sensory cilium. Through these efforts, I identified rdl-1, the C. elegans ortholog of the human disease gene Retinal Degeneration 3 (Rd3). Using in vivo imaging techniques, I determined that RDL-1 and RD3 are Golgi-associated proteins that act together with clathrin adapters to promote egress of rGCs from the Golgi. Also, I performed genetic studies of genes linked to membrane-trafficking to identify modifiers of the rdl-1 trafficking defect. Through this screen, I identified the retromer complex, which mediates retrograde transport pathway from endosomes to Golgi, as a suppressor of the rdl-1 rGC trafficking defect.

In Chapter Four of my dissertation, I examine additional molecules that were identified in the candidate genetic screen as acting along with RDL-1 in promoting rGC traffic to the sensory cilium. This section includes a summary of a proteomic study of molecules that interact either with RDL-1 or with the receptor-type cyclase GCY-9 and that might function in promoting cyclase transport to the cilium.

Indexing (document details)
Advisor: Ringstad, Niels
Commitee: Barr, Maureen, Chao, Moses V., Nance, Jeremy F., Salzer, James L.
School: New York University
Department: Basic Medical Science
School Location: United States -- New York
Source: DAI-B 79/02(E), Dissertation Abstracts International
Subjects: Neurosciences, Genetics, Cellular biology
Keywords: Carbon dioxide, Cellular trafficking, Golgi, Guanylate cyclase, Sensory cilium, Signal transduction
Publication Number: 10618951
ISBN: 978-0-355-40769-3
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