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Protocadherin-gamma (Pcdh-γ) and its role in sensory axons and epidermal reinnervation
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- Author / Creator
- Ong, Honyi
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Peripheral nerve injuries (PNI) and peripheral nerve diseases/neuropathy (PND) are common clinical conditions characterized by varying degrees of sensory, autonomic and motor dysfunctions. Despite significant advancement in microsurgical techniques to repair the injured nerves, functional recovery from PNI and PND is often suboptimal. Disabilities ranging from muscle weakness, skin numbness to chronic neuropathic pain often accompany PNI and PND patients, severely affecting their quality of life. A series of molecules and pathways are recognized to participate in axon regeneration, but one unexplored area is how those newly regrowing sensory axons reconnect and reinnervate one of their chief targets: the skin. Building on preliminary work from my former graduate student colleague, Dr. Rebecca Long, my project focuses on protocadherin-gamma (Pcdh-γ), a molecule that has been proposed by researchers to be a strong candidate to serve as cell identity marker in the mammalian nervous system. Pcdh-γ has been shown to play a role in regulating interneuron survival and synaptogenesis during developmental stages in the central nervous system (CNS). In adult mice, conditional knockout of Pcdh-γ in retinal starburst amacrine cells (SACs) and Purkinje neurons is associated with neurite self-avoidance defects and fasciculation of dendrites. In pyramidal neurons, however, conditional knockout of Pcdh-γ led to dendritic simplification and thinning of cortical layers.
Current literature has yet to study Pcdh-γ in the peripheral nervous system (PNS), especially in the context of axon regeneration, given its role of directing dendrite morphology in the CNS. In this project, by using both in vitro and in vivo experiments, we explored the roles played by Pcdh-γ in sensory axons. Our in vitro experiment showed that knockdown of Pcdh-γ in uninjured DRG neurons is associated with greater neurite extension and more branchpoints per neuron. Our in vivo experiment revealed to us that footpads of mice that received Pcdh-γ
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knockdown through siRNA administration displayed greater epidermal reinnervation: higher intraepidermal nerve fiber density (IENFD). These exciting findings shed light on the potential roles of Pcdh-γ in axon regeneration/growth and skin epidermal reinnervation. In the final experiment, we studied Rac1 as a potential downstream signaling molecule of Pcdh-γ knockdown. We proposed that Rac1 inhibition might attenuate those axon morphological changes we observed from the knockdown of Pcdh-γ. The greater total neurite extension and branchpoints per neuron that resulted from Pcdh-γ knockdown were indeed nullified with Rac1 inhibition. Ultimately, by understanding the molecular mechanisms of Pcdh-γ in skin epidermal reinnervation, a new molecular approach to treat PNI and PND could be discovered. -
- Graduation date
- Fall 2022
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.