Identification and characterization of oligodendrocyte precursor cell hypercellularity and its relevance to glioma initiation
Abstract/Contents
- Abstract
- Oligodendrocyte precursor cells (OPCs) are a progenitor population located throughout the brain that serve vital functions in development and plasticity. Recently, OPCs have garnered substantial attention as a putative cell-of-origin for a variety of gliomas, including glioblastoma multiforme. It is crucial to understand the mechanisms that govern the transformation of OPCs in order to better inform therapeutic strategies. Unfortunately, little is known about the processes by which OPCs transition from healthy to neoplastic. One of the most promising avenues of pursuit involves the tumor suppressor gene Nf1. It has been demonstrated that Nf1 gene loss increases OPC density and proliferation. Therefore, we hypothesized that Nf1 may serve a particularly important role in regulating OPC density and, in turn, will highlight important signaling pathways that are drivers of gliomagenesis. Using a Nf1 heterozygous mouse model, we discovered a striking phenotype whereby OPCs formed discrete, hyperdense foci. These foci (which we call hypercellular lesions) are particular to OPCs, as other glial cell types within the brain do not display the same clustering behavior in this model. Similarly, Nf1 dysfunction is necessary for this behavior, as heterozygous models of other tumor suppressor genes did not induce this phenotype. By targeting Nf1 loss to OPCs specifically, we demonstrated that hypercellular lesions develop due to cell-intrinsic dysfunction. This signaling is caused by overactive Ras signaling through the PI3K pathway. Moving to in vitro assays, we demonstrated that Nf1-deficient OPCs have reduced process extension. This is significant since OPCs are highly ramified cells that utilize their processes to survey their microenvironment and make decisions. This monitoring allows for OPCs to properly identify signals to proliferate, differentiate, and senesce. Therefore, altered function of OPC processes following Nf1 loss may have substantial effects on their cellular activities. We demonstrate that this reduction in process extension corresponds to increased proliferation and decreased differentiation in Nf1 knockout OPCs. To further probe the effect of Nf1 loss of OPC activity, we performed RNA sequencing of OPCs that were either wild-type (WT), heterozygous, or Nf1 knockout. Our results indicate that Nf1 loss leads to abnormal netrin signaling. Netrin is a known chemorepulsive cue that is involved in the dispersion of OPCs within the developing spinal cord. We found that exposure of Nf1-deficient OPCs to netrin led to increased proliferation and altered process extension relative to WT OPCs. These results suggest that Nf1 loss and subsequent transcriptional changes may allow for OPCs to hijack this chemorepulsive cue to promote their own growth. In summary, we discovered a phenotype whereby Nf1 heterozygous mice develop hypercellular OPC lesions that may inform both mechanisms of gliomagenesis as well as OPC homeostasis. Future work will enable for a better understanding of the processes by which OPCs transform from healthy to neoplastic, potentially uncovering new targets for therapeutic pursuit.
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 | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Lennon, James |
|---|---|
| Degree supervisor | Monje-Deisseroth, Michelle |
| Thesis advisor | Monje-Deisseroth, Michelle |
| Thesis advisor | Attardi, Laura |
| Thesis advisor | Palmer, Theo |
| Degree committee member | Attardi, Laura |
| Degree committee member | Palmer, Theo |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | James J. Lennon. |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by James Lennon
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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