Myelination in the central nervous system is fine-tuned by an antagonistic interaction between lysosomal regulators
Abstract/Contents
- Abstract
- Myelination by oligodendrocytes is critical for fast axonal conduction and for the support and survival of neurons; without it, the complex vertebrate nervous system could not have evolved. Recent studies have emphasized that myelination in the central nervous system is plastic and that new myelin is formed throughout life, a fact that is crucial for our approach to targeting demyelinating diseases such as multiple sclerosis. Nonetheless, the mechanisms that regulate the development of myelin by oligodendrocytes remain incompletely understood. In order to uncover new genetic players in myelination, we carried out a forward genetic screen using zebrafish. This study revealed that the lysosomal G protein RagA is necessary for CNS myelination. Moreover, we discovered that the lysosomal regulator TFEB represses myelination downstream of RagA, and that loss of TFEB function leads to ectopic developmental myelination. This finding defined novel essential regulators of myelination, but left remaining questions regarding exactly how TFEB represses myelination, and what steps of oligodendrocyte development are affected by TFEB. In a subsequent study, we demonstrated that TFEB regulates oligodendrocyte differentiation as well as specific parameters such as the number and length of myelin sheaths formed by individual cells. In the dorsal spinal cord of zebrafish embryos, loss of TFEB function causes oligodendrocytes to produce fewer myelin sheaths, and these sheaths are longer than those produced by wildtype cells. In contrast, oligodendrocytes lacking RagA function produce shorter myelin sheaths. We also showed that RagA and TFEB act antagonistically, such that animals lacking both RagA and TFEB activity have myelin sheaths that are similar in length to control animals. Finally, preliminary transcriptional analysis suggests that the downstream targets of TFEB that are affecting myelination may not be lysosomal in nature, as would be expected given what is known about TFEB as a key lysosomal regulator. Instead, TFEB may be regulating myelination via cytoskeletal dynamics or calcium signaling, both of which have been previously found to be important in myelination. Future work on these TFEB targets has the potential to elucidate novel biological pathways that are critical for the understanding of myelination.
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 | Bouchard, Ellen Lara |
|---|---|
| Degree supervisor | Talbot, William S |
| Thesis advisor | Talbot, William S |
| Thesis advisor | Kingsley, David M. (David Mark) |
| Thesis advisor | Villeneuve, Anne, 1959- |
| Thesis advisor | Zuchero, J |
| Degree committee member | Kingsley, David M. (David Mark) |
| Degree committee member | Villeneuve, Anne, 1959- |
| Degree committee member | Zuchero, J |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Developmental Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Ellen Lara Bouchard. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/xr024yd5721 |
Access conditions
- Copyright
- © 2023 by Ellen Lara Bouchard
- License
- This work is licensed under a Creative Commons Attribution Non Commercial Share Alike 3.0 Unported license (CC BY-NC-SA).
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