Investigating Novel Roles for gdf6 and crx in Retinal Development and Disease Open Access
- Other title
- Type of item
- Degree grantor
University of Alberta
- Author or creator
March, Lindsey D
- Supervisor and department
Andrew Waskiewicz, Biological Sciences
- Examining committee member and department
Ordan Lehmann, Medical Genetics
John Locke, Biological Sciences
Department of Biological Sciences
Molecular Biology and Genetics
- Date accepted
- Graduation date
Master of Science
- Degree level
The growth and development of an organ is a multi-step process. It involves initial specification of the progenitor cells to become a particular cell type, proliferation of those cells for organ growth, and organization of the cells into a final functional tissue. The growth and development of the vertebrate eye is an exquisite example of this process. Specification of the eye field early in development, proliferation of retinal progenitor cells and eye morphogenesis, differentiation of mature neural (retinal) and non-neural cell types that make up the eye, and organization of multiple cell types into functional tissues are required for correct eye development.
Bone morphogenetic proteins (BMPs) have diverse roles in development, including regulation of differentiation, proliferation and cell survival. Mutations in BMP genes are associated with a spectrum of blinding ocular abnormalities, including MAC (microphthalmia, anophthalmia, colobomata) and Leber’s congenital amaurosis (LCA). We used a microphthalmic zebrafish line, with a mutation in the BMP ligand gdf6a, to investigate the development of microphthalmia. gdf6a-/- mutants have ectopic retinal apoptosis that is rescued by pharmaceutical treatment with an anti-apoptotic compound. Interestingly, the rescue of retinal apoptosis in the gdf6a-/- mutants does not rescue eye-size, and only partially recovers visual activity. We concluded that mutations in gdf6a must disrupt multiple developmental processes that contribute to eye development, one of which is retinal progenitor cell survival, and that these are the underlying causes of microphthalmia in this model.
The vertebrate retina is a highly organized and laminar structure, the development of which is conserved among all vertebrates. The retina contains 6 neuronal cell types and one glial cell type. Differentiation of these cell types from retinal progenitor cells requires the transcription factor cone-rod homeobox (crx). crx is a member of the highly conserved orthodenticle-related (otx) gene family of transcription factors and lesions in human CRX have been associated with photoreceptor degeneration disorders such as LCA, retinitis pigmentosa and cone-rod dystrophy. We hypothesized that zebrafish crx-/- mutants would display a loss of photoreceptor identity. Contrary to our hypothesis, zebrafish crx-/- mutant retinas have a wild-type appearance. Zebrafish crx, and a paralog of crx, otx5, have similar expression patterns in the retina. Knocking down otx5 in crx-/- mutants revealed a loss of photoreceptor identity. We show that crx and otx5 have overlapping functions in the retina, and that Crx and Otx5 cooperatively specify photoreceptor identity in the zebrafish retina.
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- Citation for previous publication
Asai-Coakwell, M., March, L., Dai, X.H., Duval, M., Lopez, I., French, C.R., Famulski, J., De Baere, E., Francis, P.J., Sundaresan, P., Sauve, Y., Koenekoop, R.K., Berry, F.B., Allison, W.T., Waskiewicz, A.J. and Lehmann, O.J., 2013. Contribution of growth differentiation factor 6-dependent cell survival to early-onset retinal dystrophies. Hum Mol Genet. 22, 1432-42.French, C.R., Stach, T.R., March, L.D., Lehmann, O.J. and Waskiewicz, A.J., 2013. Apoptotic and proliferative defects characterize ocular development in a microphthalmic BMP model. Invest Ophthalmol Vis Sci. 54, 4636-47.Pant, S.D., March, L.D., Famulski, J.K., French, C.R., Lehmann, O.J. and Waskiewicz, A.J., 2013. Molecular mechanisms regulating ocular apoptosis in zebrafish gdf6a mutants. Invest Ophthalmol Vis Sci. 54, 5871-79.
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