A Bi-directional negative feedback loop govern the orientation of planar polarity in the drosophila wing
- Gandhy Pierre-Louis.
- Dec. 2014.
- Physical description
- online resource (x, 116 pages) : illustrations (some color)
- Pierre-Louis, Gandhy.
- Axelrod, Jeffrey (Jeffrey David). thesis advisor (primary).
- Fuller, Margaret T., 1951- thesis advisor.
- Nusse, Roel, 1950- thesis advisor.
- Simon, Michael (Michael A.) (Biologist). thesis advisor.
- Stanford University. Department of Developmental Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references.
- Epithelial cells sometimes display polarity along the axis orthogonal to the apicobasal axis -- a phenomenon referred to as planar cell polarity (PCP). This polarization biases organization of the cytoskeleton, and is required for a range of fundamental processes including, but not limited to, oriented cell division, polarized function of cilia, and the control of collective cell migration events during development. Consequently, deregulation or dysfunction of PCP genes has been linked to disorders including deafness as a result of misorientation of inner ear cells, neural tube closure defects because of a failure to execute convergent & extension, and tumor invasiveness. Despite having identified some of the key proteins required to achieve PCP, much is still unknown about their molecular functions. Evolutionarily conserved proteins, known as the core PCP proteins, are distributed asymmetrically within wing epithelial cells and form complexes within the proximal or distal cortical domains. Here, we demonstrate that these diametrically opposed complexes participate in a bi-directional negative feedback loop that simultaneously produces their asymmetric distribution within cells and reinforces the orientation of polarity to neighbors by transmitting polarity information intercellularly. We found that one of the core PCP proteins, Prickle (Pk), is important for negative feedback as it is required to mediate the exclusion of distal and proximal complexes from the plasma membrane during acquisition of asymmetry. Moreover, we found that the level of Pk is regulated by the Cullin1 (Cul1)/SkpA/Supernumerary limbs (Slimb) E3 ubiquitin ligase complex. Our observations lead us to believe that loss of, or excess, Pk perturbs PCP signaling through the disruption of feedback. Ultimately, these results highlight an underlying molecular mechanism for the generation of planar polarity. Finally, the approaches presented in this monograph can further help elucidate the molecular functions of the other core PCP proteins.
- Publication date
- Submitted to the Department of Developmental Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2014.