The Role of Ciliopathy Genes in Axonal Development
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2022-01-26
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Abstract
Primary cilia are tiny, microtubule-based organelles that project from the body of all mammalian cells and function as the cellular signalling hub. Genetic mutation of ciliary genes leads to multi-organ system dysfunction causing a group of diseases called ciliopathies. Notably, ciliopathy patients present with severe neurological phenotypes, including intellectual disability and prominent axon tract defects, suggesting a role for primary cilia in axonal development. However, the mechanisms behind axonal phenotypes in ciliopathies are not well understood. The formation of axons requires the assembly of very long microtubules, which are nucleated by the centrosome. As the cell’s microtubule organizing centre and the organelle that forms the base of the primary cilium, the centrosome is a common link between the axonal cytoskeleton and the cilium. Therefore, I hypothesized that the loss of ciliary proteins could impact the microtubule cytoskeleton, which in turn could influence axonal morphology and microtubule-based trafficking. This thesis investigates the role of two proteins that localize to the centrosome and base of the cilium, Ahi1 and Bbs7, in axonal development. Using targeted shRNA gene knockdown in cortical mouse neurons, I first investigated the roles of Ahi1 and Bbs7 in axonal morphology. Then, I further analyzed the role of Ahi1 in axons, using live cell imaging to examine axonal trafficking along microtubules. This thesis provides evidence that initial axonal outgrowth and axonal branching are inhibited by ciliary gene knockdown. I also present evidence that the trafficking of early endosomes and synaptic vesicles along axonal microtubules is altered by Ahi1 deficiency, which could impact axon growth, health, and synaptic function. Further research will be necessary to understand the exact cause and consequences of these changes in axonal morphology and trafficking; however, this thesis substantiates a role for primary cilia in regulating the developing axon.
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Catalano, C. N. (2022). The Role of Ciliopathy Genes in Axonal Development (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.