Student Theses and Dissertations
Date of Award
2025
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Shai Shaham
Keywords
glia-neuron communication, amphid, Hedgehog-like signaling, WRT-6, PTC-1, C. elegans
Abstract
Complex organisms rely on their nervous systems to sense their environment, process the gathered information, and execute appropriate responses. Glia play essential roles in this information transduction, and glia-neuron communication regulates sensation at every step. But despite this centrality of glia in nervous system function, many of the molecular mechanisms through which glial cells establish and maintain reciprocal communication with neurons are unknown. C. elegans sensory organs provide a good model to study glia-neuron crosstalk. The largest one in the animal is called the amphid and acts somewhat like a nose for the worm. Amphid neurons are integral to sensing odorants, salts, and other environmental cues that the animal needs to assess for successful feeding, reproduction, and escaping harmful conditions. In these roles, amphid neurons rely heavily on their two glial partners, a sheath and a socket glia of the amphid. These glia are involved in both the proper structural development and the functioning of amphid sensory organ throughout the animal's life. In this thesis, I pursued various lines of inquiry that led me to a novel glia-neuron signalling pathway that regulates neuronal properties in very specific ways. Two key players in this mechanism are WRT-6, a Hedgehog-like protein secreted by the socket glia, and PTC-1, a Patched homolog found in the amphid neurons. It is believed that C. elegans, lacking bona fide homologs of Hedgehog and Smoothened, does not possess the canonical Hedgehog signalling pathway that has been evolutionarily conserved across a wide range of organisms. However, our results suggest that a non-canonical Hedgehog-like signalling might in fact be present in the worm's nervous system, with a function in glia-neuron communication. Other players in this hypothesized pathway include SUP-17 and TSP-14 in the socket glia, FIG-1 and VAP-1 in the sheath glia, and Y9 in the amphid neurons. SUP-17 is a homolog of the ADAM10 metalloprotease, and TSP-14 is a homolog of TspanC8 tetraspanin family, which are known to modulate the maturation, localisation, and function of ADAM10. FIG-1 does not have a clear homolog in mammals, but its structure loosely resembles a mash-up of ADAM and ADAMTS proteins. VAP-1 belongs to the cysteine-rich secretory protein (CRISP)-related family, which have been implicated in cholesterol metabolism and cancer progression. Finally, Y9 is a novel 7-transmembrane protein I've described that is found on the cilia of a subset of the amphid neurons, which I speculate might function as a Smoothened-like protein. The findings from my thesis work favour a model in which these various glial and neuronal proteins affect each other's cleavage, localisation, and/or function through direct and indirect mechanisms. Furthermore, I believe that a key molecular component of this complex regulation is cholesterol, or another sterol molecule, which is known to be central for canonical Hedgehog signalling. The sum of these interactions constitutes a Hedgehoglike signalling pathway between the glia and neurons of the amphid sensory organ. The neuronal processes controlled by this pathway are currently ill-understood, however one readout for them is whether the amphid neurons are able to incorporate lipophilic dye molecules to their plasma membranes. Uncovering more players and molecular mechanisms related to this signalling pathway has the potential not only to provide important insight into glia-neuron communication, but also to elucidate long-remaining mysteries regarding Hedgehog evolution in nematodes and potentially establish C. elegans as a promising model for the study of non-canonical Hh signalling in the nervous system.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Magemizoğlu, Elif, "Hedgehog - like Proteins are Involved in a Novel Glia - Neuron Signalling Pathway in C. elegans" (2025). Student Theses and Dissertations. 814.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/814
Comments
A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy