Doctor of Philosophy
Dr. Sashko Damjanovski
Peroxisomes are organelles whose roles in fatty acid metabolism and reactive oxygen species (ROS) elimination have contributed much attention in understanding their origin and biogenesis. Many studies have shown that de novo peroxisome biogenesis is an important regulatory process, while yeast studies suggest that total peroxisome numbers are in part regulated by proteins such as Pex11, which can facilitate the division of existing peroxisomes. Although de novo biogenesis and divisions are likely important mechanisms to peroxisome functioning, the regulation of peroxisome numbers during embryonic development is poorly understood. Peroxisome number and function are particularly crucial in oviparous animals such as frogs where large embryonic yolk and fatty acid stores must be quickly metabolized, and ROS eliminated. The central role of peroxisomes with respect to ROS is in the generation and scavenging of hydrogen peroxide. Recent studies have revealed their involvement in metabolism of oxygen free radicals that have important functions in cell signaling. Using Xenopus laevis as a developmental model, this study demonstrates that overexpression and inhibition of Pex11β directly increases and decreases peroxisome number in vitro, and induces an early- or delayed-onset to peroxisome biogenesis in vivo, respectively. Knockdown of Pex11β, decreasing peroxisome numbers, induced a bent/double-axis phenotype compared to that of control uninjected embryos. This phenotype has previously been linked to increases in the redox sensitive-noncanonical Wnt/Planar Cell Polarity (PCP) cell signaling. As a result, this study investigated if changes in peroxisome number could affect intracellular ROS levels, thereby activating redox-sensitive cell signaling pathways such as canonical and noncanonical Wnt signaling. Following inhibition of Pex11β, there were significant increases in ROS levels in X. laevis A6 cells. I show for the very first time that changes in cellular ROS levels, as a result of decreases in peroxisome numbers, perturb noncanonical Wnt cell signaling.
Fox, Mark A., "The role of Pex11-beta in peroxisome biogenesis, intracellular relationship to reactive oxygen species levels and redox-sensitive cell signaling" (2012). Electronic Thesis and Dissertation Repository. 461.