Dissertation under the direction of Professor Bruce H. Appel
Oligodendrocytes are specialized glial cells in the vertebrate central nervous system (CNS) that extend processes to wrap axons in myelin sheaths. Their number and distribution must be regulated to ensure uniform axon myelination for rapid conduction of nerve impulses. Elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells, but the mechanisms that limit Notch activity to balance formation of neurons and glia from neural precursors are poorly understood. By screening for zebrafish mutations that disrupt oligodendrocyte development we found one allele, called vu56, which produced excess oligodendrocyte progenitor cells (OPCs). Positional cloning revealed that vu56 is a mutation of fbxw7 (f-box protein and wd repeat domain-containing 7), which encodes the substrate recognition component of a ubiquitin ligase that targets Notch for degradation. To investigate the basis of the mutant phenotype we performed in vivo, time-lapse imaging, which revealed that the increase in OPC number resulted from production of extra OPCs by ventral spinal cord precursors and not from changes in OPC proliferation or death. Notch signaling activity was elevated in spinal cord precursors of fbxw7 mutant zebrafish and inhibition of Notch signaling suppressed formation of excess OPCs. Our data indicate that Fbxw7 helps attenuate Notch signaling during zebrafish neural development thereby limiting the number of OPCs.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07182013-211934 |
| Date | 29 July 2013 |
| Creators | Snyder, Julia Lynn |
| Contributors | Michael Cooper, Bruce Carter, Charles Singleton, Kendal Broadie, Bruce Appel |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07182013-211934/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.1524 seconds