The zebrafish visual system relies on positional information in the retina and optic tectum, so that the spatial fidelity of light signals that enter the eye are preserved for visual processing. This positional information is essential for ordered topographic mapping of retinal ganglion cell axons. Spatial information in the retina and tectum relies on discrete signaling pathways that regulate polarized expression of axon guidance molecules in distinct domains in both the retina and tectum, thereby ensuring that accurate topographic maps are created.
In this thesis, I have investigated the function of two families of transcription factors, Pbx and Meis, as well as a growth factor of the Bmp family, Gdf6a, in specifying positional identity in the zebrafish visual system. I demonstrate that two partially redundant pbx genes, pbx2 and pbx4, along with members of the meis family, are required for patterning of the dorsal retina and tectum in zebrafish. Embryos lacking these critical transcription factors exhibit retinal ganglion cell axon outgrowth errors, which are likely the result of tectal mis-patterning.
Bone morphogenetic protein (Bmp) growth factors regulate dorsal retinal identity in vertebrate models, but the developmental timing of this signaling remains unclear. In this thesis, I investigate the functions of two zebrafish Bmps, Gdf6a and Bmp4, during initiation of dorsal retinal identity. Knockdown of zebrafish Gdf6a blocks initiation of dorsal marker expression, while knockdown of Bmp4 produces no discernable retinal phenotype. These data, combined with analyses of embryos ectopically expressing Bmps, demonstrate that Gdf6a is necessary and sufficient for initiation of dorsal retinal identity, and loss of such identity leads to errors in retinal ganglion cell topographic mapping.
Finally, I demonstrate that gdf6a is required for numerous embryonic processes in addition to dorsal retina specification. Gdf6a in required for eye growth, as loss of Gdf6a function leads to microphthalmia. I have obtained preliminary evidence that this growth factor is also required for development of the lens and axial skeleton. Furthermore, many of these phenotypes are similar to those seen in human patients with mutations in GDF6, highlighting the importance of understanding the function of this growth factor in model organisms. / Molecular Biology and Genetics
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1509 |
| Date | 11 1900 |
| Creators | French, Curtis Robert |
| Contributors | Dr. Andrew Waskiewicz (Department of Biological Sciences, University of Alberta), Dt. W. Ted Allison (Department of Biological Sciences, University of Alberta), Dr. Shelagh Campbell (Department of Biological Sciences, University of Alberta), Dr. Ordan Lehmann (Department of Medical Genetics, University of Alberta), Dr. James Fadool (Department of Biological Sciences, Florida STate University) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 96575811 bytes, application/pdf |
| Relation | French CR, et al., BMC Dev Biol. 2007, 7:85., French CR et al., Dev Biol. 2009, 333(1):37-47., Asai-Coakwell M, French CR et al., Hum Mol Genet. 2009, 18(6):1110-21., Asai-Coakwell M, French CR et al., Am J Hum Genet. 2007, 80(2):306-15. |
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