An E-cadherin and PAR-3-based symmetry breaking mechanism translates stable cell/cell contacts into coordinate tissue polarity in C. elegans intestinal epithelial cells
Abstract/Contents
- Abstract
- Tissue-wide patterning is essential to multicellular development, requiring cells to individually generate polarity axes and coordinate them in space and time with neighbors. One of the most prevalent animal tissues are epithelia, which polarize along a characteristic apico-basolateral axis and are critical for protecting internal organs from the external environment. The mechanisms which 'break symmetry' and inform the orientation and execution of apico-basolateral polarity axes across diverse epithelia remain poorly understood. To address these questions, I explored symmetry breaking in the developing Caenorhabditis elegans intestine, a simple epithelial tube which gains its polarity as a sixteen-celled primordium when apical proteins polarize along a central embryonic midline. After introducing general principles of epithelial polarity (Chapter 1) and development of the worm intestine (Chapter 2), I describe essential roles I found for the polarity scaffold PAR-3 and the transmembrane adhesion protein HMR-1/E-cadherin in epithelial symmetry breaking (Chapter 3). C. elegans intestinal cells break their symmetry as an 8-celled primordium when they localize PAR-3 and HMR-1 into large puncta I term Local Polarity Complexes (LPCs). By pairing detailed imaging approaches with powerful genetic tools to remove LPC components specifically in the intestine, I discovered that PAR-3 and HMR-1 function as an interdependent module to build LPCs during, but that these factors diverge in function to elaborate tissue polarity. In Chapter 4, I describe how asymmetric information is transmitted to intestinal cells to mark the first meaningful polarity cue within the tissue. I found that LPCs mature exclusively at homotypic (intestine/intestine) contacts and are largely absent from heterotypic (intestine/neighbor) contacts. Through careful analysis of high temporal resolution developmental movies and acute perturbations with chemical inhibitors, I showed that symmetry breaking is mediated by inherent differences in contact stability: LPCs can form at all intestinal surfaces but are systematically removed from heterotypic contacts via neighbor rearrangements and oriented cell division. This work reveals a novel 'molecule-agnostic' symmetry breaking paradigm for an internally developing epithelium. Finally, I demonstrate the existence of backup mechanisms which eventually polarize intestinal primordia which lack HMR-1 (Chapter 5), and describe a proof-of-concept forward genetic screening approach to reveal interactors working in concert with or parallel to HMR-1.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Naturale, Victor Frank |
|---|---|
| Degree supervisor | Feldman, Jessica L |
| Thesis advisor | Feldman, Jessica L |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Shen, Kang, 1972- |
| Thesis advisor | Simon, Michael, (Biology professor) |
| Degree committee member | Oro, Anthony, 1958- |
| Degree committee member | Shen, Kang, 1972- |
| Degree committee member | Simon, Michael, (Biology professor) |
| Associated with | Stanford University, School of Humanities and Sciences |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Victor F. Naturale. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/jk514tr0962 |
Access conditions
- Copyright
- © 2023 by Victor Frank Naturale
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...