Author ORCID Identifier
Date of Award
Doctor of Philosophy in Biology - (Ph.D.)
Federated Department of Biological Sciences
Jennifer Rebecca Morgan
When neural tissue is injured by trauma, delicate neuronal processes such as axons and dendrites are prone to lesion damage and often disconnect. The molecular, cellular, and circuit mechanisms that underlie the regrowth and reconnection of these processes and the recovery of behavior are major challenges in the fields of neuroscience, regeneration, and resilience. At the molecular and cellular levels, signaling pathways that mediate neuronal growth cone guidance during development can play a role in neuronal regeneration and recovery from injury. One family of signaling proteins involved in this process comprises the highly conserved semaphorins and their receptors, the plexins. Across various species, from C. elegans to humans, semaphorins and plexins are crucial for axon pathfinding and synapse formation during development.
In the mammalian nervous system, the semaphorin signaling system is comprised of more than 20 semaphorins and 9 plexins, whereas the C. elegans genome only encodes 3 semaphorins and 2 plexin receptors. Among them, the transmembrane semaphorins, SMP-1 and SMP-2, signal through their receptor PLX-1, while the secreted semaphorin MAB-20, signals through PLX-2.
This dissertation explores the role of semaphorin signaling in neuroregeneration in vivo, by making use of the experimental advantages of Caenorhabditis elegans. Importantly, this versatile model animal has the natural ability to regenerate neuronal processes after injury and optic methods were developed to precisely disconnect single neurites in otherwise intact animals using laser microsurgery. Moreover, the semaphorin system is relatively simple and genetically amenable, and transgenic, microscopy and behavior analysis methods are well established.
The development and assessment of a new laser microsurgery system as part of this thesis allowed reliable and accurate disconnection of identifiable axons and dendrites. The elucidated expression patterns and involvement of C. elegans semaphorins in neural regeneration have shed significant light with regard to the role this pathway plays in C. elegans regeneration and added to the field of knowledge of neural regeneration research.
The findings reveal that regrowth and reconnection are more prevalent in the absence of both plexin receptors and the secreted semaphorin MAB-20. This suggests that the semaphorin signaling in this system restricts neural growth, possibly to prevent aberrant reconnection. The membrane-bound SMP-1 and SMP-2 might have a redundant role, signaling through PLX-1. These results align with the inhibitory effects of semaphorin signaling on axonal growth and guidance during development in the mammalian system. Therefore, secreted and membrane-bound semaphorin signaling pathways restrict regeneration using distinct processes, likely involving spatial specificity and recurrent signals.
Findings such as the ones presented in this thesis delve deeper into the mechanisms and factors involved in promoting regeneration and aid to uncover valuable insights that could assist in overcoming the challenges faced by regenerative medicine in treating central nervous system injuries and disorders.
Harreguy Alfonso, Maria Belen, "The role of semaphorins in response to injury in C. elegans neurons" (2023). Dissertations. 1714.