Morphogenesis of tissues requires coordinated cell behaviors that often occur in a planar polarized (PCP) fashion. Defects in polarized morphogenesis underlie various human pathologies including birth defects associated with open neural tubes. While the signaling pathway that generates PCP pattern is increasingly well-understood, we have little information about the mechanisms through which this patterning drives PCP morphogenesis. The long- term goal of this project is to understand these mechanisms in order to reveal how polarization of cells and their morphogenetic behaviors gives final form to a developing tissue. Elongation of the Drosophila egg is a simple but little-studied process that requires PCP morphogenesis in the ovarian follicle cell epithelium. This process shares several cellular features with important vertebrate morphogenetic movements, including a PCP cytoskeleton, the involvement of the extracellular matrix, and the extension of polarized cellular protrusions. Surprisingly, despite the PCP organization of cytoskeleton, matrix, and protrusions, neither these features nor egg elongation itself requires the core genes of the canonical PCP pathway. Through a forward genetic screen, we have discovered three new regulators of egg elongation that are linked to PCP and its developmental outcomes. We hypothesize that these define an intracellular signaling pathway that directs PCP elongation of the developing egg. To test this hypothesis, and to uncover the hierarchy governing and executing this PCP morphogenetic event, we will use the following strategies. We will employ high-definition morphometric analysis of fixed and live samples to define the ontogeny and dynamic behavior of cellular protrusions. We will use genetic, molecular and cell biological approaches to identify the role of the novel regulators in organizing protrusions, cytoskeleton, extracellular matrix, and other PCP features of the follicle cells and to place them into a regulatory pathway. Finally, we will carry out a large genetic screen to identify and characterize additional novel factors involved in egg elongation. Overall, our studies will shed light on the poorly-understood general mechanisms by which PCP organization drives tissue morphogenesis. They will move the field forward by elucidating a mechanism of PCP morphogenesis in a novel context where genetics, cell biology, and imaging are all brought to bear. Finally, they will set the stage for a future understanding of how morphogenesis integrates both internal cellular and extracellular forces to give organs their final forms.
Proper formation of many human tissues, including closure of the neural tube, requires execution of cell movements that are polarized within the plane of an epithelial tissue. A pathway that polarizes cell surfaces in this plane has been uncovered, yet we do not understand the mechanisms by which this well- characterized planar polarity pathway actually direct the cellular behaviors that shape an organ. This proposal will explore the cellular and molecular mechanisms that lie downstream of planar cell polarity signaling to regulate morphogenesis, by exploiting the genetic manipulability of the fruit fly to understand a simple planar polarized process that confers oval rather than round shape to the fly egg.
|Bilder, David; Irvine, Kenneth D (2017) Taking Stock of the Drosophila Research Ecosystem. Genetics 206:1227-1236|
|Katheder, Nadja S; Khezri, Rojyar; O'Farrell, Fergal et al. (2017) Microenvironmental autophagy promotes tumour growth. Nature 541:417-420|
|Chen, Dong-Yuan; Crest, Justin; Bilder, David (2017) A Cell Migration Tracking Tool Supports Coupling of Tissue Rotation to Elongation. Cell Rep 21:559-569|
|Crest, Justin; Diz-Muñoz, Alba; Chen, Dong-Yuan et al. (2017) Organ sculpting by patterned extracellular matrix stiffness. Elife 6:|
|Chen, Dong-Yuan; Lipari, Katherine R; Dehghan, Yalda et al. (2016) Symmetry Breaking in an Edgeless Epithelium by Fat2-Regulated Microtubule Polarity. Cell Rep 15:1125-33|
|Bilder, David (2016) The Maturation of Development. Dev Cell 38:569-70|
|Skwarek, Lara C; Windler, Sarah L; de Vreede, Geert et al. (2014) The F-box protein Slmb restricts the activity of aPKC to polarize epithelial cells. Development 141:2978-83|
|de Vreede, Geert; Schoenfeld, Joshua D; Windler, Sarah L et al. (2014) The Scribble module regulates retromer-dependent endocytic trafficking during epithelial polarization. Development 141:2796-802|
|O'Brien, Lucy Erin; Bilder, David (2013) Beyond the niche: tissue-level coordination of stem cell dynamics. Annu Rev Cell Dev Biol 29:107-36|
|Buster, Daniel W; Daniel, Scott G; Nguyen, Huy Q et al. (2013) SCFSlimb ubiquitin ligase suppresses condensin II-mediated nuclear reorganization by degrading Cap-H2. J Cell Biol 201:49-63|
Showing the most recent 10 out of 31 publications