Identifying frizzled receptors that are essential for intestinal stem cell maintenance
Abstract/Contents
- Abstract
- The mammalian small intestinal epithelium is a rapidly self-renewing tissue with a high turnover rate maintained by intestinal stem cells that reside at the base of glands called crypts. The intestinal epithelium is notably dependent on canonical Wnt/b-catenin signaling. Wnt proteins are evolutionarily conserved, secreted ligands that regulate cell-cell communication during developmental and adult tissue homeostasis. Wnt binding to its receptor Frizzled (Fzd) and co-receptors Lrp5/6 initiates canonical (i.e. Wnt/b-catenin) signaling. Our lab and others have shown that inhibition of Wnt ligands, receptors, or downstream signaling leads to the loss of intestinal crypts and Lgr5+ intestinal stem cells (ISCs) indicating that Wnt signaling is critical for ISC maintenance. To date, 19 Wnt ligands and 10 Fzd receptors have been discovered in mammals. However, due to extensive cross-reactivity among Wnt ligands and Fzd receptors, it is unclear which Fzds are functionally relevant in ISC biology. In addition, it is not known which intestinal cell types are responsible for expressing functionally important Fzd receptors for stem cell maintenance. Understanding the mechanisms of Wnt activation in ISC maintenance will allow us to finely regulate Wnt signaling to promote regeneration following intestinal epithelial damage from diseases or harsh treatments such as radiation or chemotherapy. Furthermore, since dysregulations of Wnt/b-catenin signaling are frequently found in gastrointestinal diseases including inflammatory bowel diseases and cancers, addressing these questions holds tremendous potential for translational applications. Our lab has been collaborating with Dr. Chris Garcia's lab at Stanford to better understand intestinal stem cell biology, and his lab has recently bioengineered Wnt agonists and antagonists that mediate Wnt signaling in a Fzd-subtype specific manner. Using these novel proteins as initial screening tools, I will present work identifying Fzd subtypes essential for ISC maintenance in vitro and in vivo. I will further identify cell types that express the corresponding Fzd receptors by using intestinal organoid culture systems and genetic mouse models. First, I define essential Fzds necessary for ISC maintenance using Wnt antagonists as loss-of-function probes. Next, I characterize the molecular mechanism of stem cell and crypt/villus loss induced by Wnt-Fzd complex disruption. Lastly, I deploy Wnt agonists as gain-of-function probes to evaluate the therapeutic potential of Wnt as a replacement for endogenous Wnt in ISCs and in the transplantation setting. Collectively, this dissertation thesis presents fundamental molecular insights into Wnt signaling mechanisms with the ultimate goal of understanding Fzd specificity in the intestinal stem cell compartment.
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 | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Ha, Andrew |
|---|---|
| Degree supervisor | Kuo, Calvin Jay |
| Thesis advisor | Kuo, Calvin Jay |
| Thesis advisor | Bergmann, Dominique |
| Thesis advisor | Dunn, James |
| Thesis advisor | Red-Horse, Kristy |
| Degree committee member | Bergmann, Dominique |
| Degree committee member | Dunn, James |
| Degree committee member | Red-Horse, Kristy |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Andrew Ha. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2020. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Andrew Ha
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