The contribution of myelin lipids to the failure of central nervous system axon regeneration
Abstract/Contents
- Abstract
- CNS myelin is strongly inhibitory to growing axons and is presently thought to be a major contributor to CNS axon regenerative failure. Although a number of proteins present in myelin, including Nogo, MAG and OMgp, have been identified as myelin-associated inhibitors, studies of mice lacking these genes suggest that additional inhibitors present in CNS myelin remain to be identified. Here, I have investigated the hypothesis that myelin lipids contribute to CNS regenerative failure. I identified sulfatide, a major constituent of CNS myelin, as a novel myelin-associated inhibitor of neurite outgrowth. Sulfatide, but not galactocerebroside or ceramide, strongly inhibited the neurite outgrowth of retinal ganglion cells (RGCs) when used as a purified lipid substrate. The mechanism involved in sulfatide-mediated inhibition shared features with other known inhibitors, as the stabilization of GTP-bound Rho was required for inhibition. Myelin in which sulfatide was lacking or blocked using specific antibodies was significantly less inhibitory to RGC neurite outgrowth in vitro than was wild type myelin, indicating that sulfatide is a major component of CNS myelin's inhibitory activity. Mice unable to make sulfatide did not regenerate RGC axons more robustly after optic nerve crush than wild type littermates under normal conditions, but did exhibit a small but significant enhancement in the extent of zymosan-induced regeneration. These results demonstrate that specific lipids can powerfully inhibit axon growth, identify sulfatide as a novel myelin-associated axon growth inhibitor, and provide evidence that sulfatide inhibition contributes to axon regenerative failure in vivo.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Copyright date | 2011 |
| Publication date | 2010, c2011; 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Winzeler, Alissa Meyer |
|---|---|
| Associated with | Stanford University, Department of Developmental Biology. |
| Primary advisor | Barres, Ben |
| Thesis advisor | Barres, Ben |
| Thesis advisor | Fuller, Margaret |
| Thesis advisor | Luo, Liqun, 1966- |
| Thesis advisor | McConnell, Susan K |
| Advisor | Fuller, Margaret |
| Advisor | Luo, Liqun, 1966- |
| Advisor | McConnell, Susan K |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Alissa Meyer Winzeler. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Alissa Meyer Winzeler
- 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...