NLGN3 interacts with CSPG4 through regulated intramembrane proteolysis, driving glioma growth and maintaining OPC stemness
Abstract/Contents
- Abstract
- Pediatric high-grade glioma (pHGG) is a category of lethal brain cancers, many of which are inoperable and have no specific approved treatments. Oligodendrocyte precursor cells (OPCs), the putative cell of origin for these tumors, undergo a mitogenic response to active neurons. Previous work has identified that neuronal activity increases pHGG proliferation and growth in vivo through the activity-dependent release of soluble neuroligin-3 (sNLGN3). Furthermore, previous unbiased proximity labeling and mass spectrometry has identified the proteoglycan and OPC marker chondroitin sulfate proteoglycan 4 (CSPG4) as a candidate binding partner. Here, CSPG4 as the receptor for NLGN3 on glioma cells is validated and a role for this signaling axis in healthy OPC physiology and differentiation is established. Membrane pulldown assays combined with mass spectrometry further establish CSPG4 as the NLGN3 binding partner. An in vitro protein shedding assay shows that NLGN3 interacts with CSPG4 and the complex undergoes two rounds of cleavage by the proteases ADAM10 and gamma secretase through a mechanism known as regulated intramembrane proteolysis. The resulting intracellular cascade is responsible for the mitogenic effects of NLGN3. Additionally, NLGN3 maintains OPC stemness when growth factors are withdrawn, and suppressing the NLGN3-CSPG4 axis with gamma secretase inhibition results in increased differentiation. These results identify new druggable targets in a pathway important to pHGG growth and shed light on the understudied mechanism of glial differentiation.
Description
| Type of resource | text |
|---|---|
| Date modified | December 5, 2022 |
| Publication date | May 6, 2022; May 2022 |
Creators/Contributors
| Author | Reed, James |
|---|---|
| Thesis advisor | Monje, Michelle |
| Thesis advisor | Luo, Liqun |
| Degree granting institution | Stanford University, Department of Biology |
Subjects
| Subject | Biology |
|---|---|
| Subject | Cancer |
| Subject | Neurosciences |
| Subject | Neuroglia |
| Subject | Oligodendroglia |
| Subject | Gliomas |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
Access conditions
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).
Preferred citation
- Preferred citation
- Reed, J. and Monje, M. (2023). NLGN3 interacts with CSPG4 through regulated intramembrane proteolysis, driving glioma growth and maintaining OPC stemness. Stanford Digital Repository. Available at https://purl.stanford.edu/mg620qk1438
Collection
Undergraduate Theses, Department of Biology, 2021-2022
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- Contact
- jamesree@stanford.edu
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