DOI
https://doi.org/10.25772/A6S3-TN04
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Integrative Life Sciences
First Advisor
Gregory Walsh
Abstract
Axon pathfinding is a fundamental step that establishes the vast networks of the nervous system. Understanding this process is important because disruptions to these neural networks can impair quality of life. During axon pathfinding, an axon’s growth cone comes in contact with a variety of secreted chemotropic signaling cues that control growth cone behavior through activation of signal transduction pathways which cause changes to the cytoskeleton. One such pathway is the Planar Cell Polarity (PCP) signal transduction pathway that responds to gradients of non-canonical Wnt ligands. PCP has a well-known role in axon pathfinding, including axon pathfinding in the spinal cord, where it affects anterior-posterior guidance of axons. Spinal commissural neurons are one subset of neurons that are affected by PCP-mediated Wnt gradients in the spinal cord. Commissural neurons are neurons whose axons cross-over contralaterally in bilateral animals. Since commissural neurons undergo dynamic pathfinding patterns, they are an attractive model for studying axon pathfinding and neural circuit formation. Our previous research established a role for core PCP proteins in anterior-posterior guidance of zebrafish commissural primary ascending (CoPA) neurons in the spinal cord. This study looks to expand on this research by assessing the role of PCP accessory protein Ptk7 in CoPA axon pathfinding. Ptk7 is a transmembrane receptor tyrosine kinase (RTK) protein with a non-functional intracellular tyrosine kinase domain. Here, I demonstrate that, similar to other PCP mutations, mutations in ptk7 are sufficient to cause CoPA anterior-posterior axon pathfinding defects. Moreover, using chimeric analysis, I demonstrate that Ptk7 is required both autonomously and non-autonomously for correct axon pathfinding. In addition, I preliminarily show that Ptk7 and PCP core protein Fzd may interact genetically. Finally, I demonstrate that PCP downstream effector JNK is essential for PCP-mediated axon pathfinding, and that inhibition of Sonic hedgehog (Shh) led to atypical CoPA morphological defects.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
11-24-2020