Download the full-sized PDF of Characterization of Retinoic Acid Synthesis and Signalling in Vertebrate Eye DevelopmentDownload the full-sized PDF



Permanent link (DOI):


Export to: EndNote  |  Zotero  |  Mendeley


This file is in the following communities:

Graduate Studies and Research, Faculty of


This file is in the following collections:

Theses and Dissertations

Characterization of Retinoic Acid Synthesis and Signalling in Vertebrate Eye Development Open Access


Other title
eye development
retinoic acid
Type of item
Degree grantor
University of Alberta
Author or creator
Cheng, Caroline ST
Supervisor and department
Waskiewicz, Andrew J
Examining committee member and department
Locke, John (Biological Sciences)
Stenkamp, Deborah (Biological Sciences, University of Idaho)
McDermid, Heather (Biological Sciences)
Allison, William (Biological Sciences)
Department of Biological Sciences
Molecular Biology and Genetics
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Normal eye development requires a complex series of morphological movements and ocular patterning with aberrant eye development resulting in birth defects and retinal dystrophies. Eleven percent of paediatric blindness is caused by microphthalmia (small eyes), anophthalmia (no eyes) and coloboma (incomplete optic fissure closure), collectively known as MAC. The incidence of eye birth defects is higher in developing nations where vitamin A deficiency is more prevalent. Vitamin A plays an essential role in organ development, including ocular embryogenesis. The biologically active derivative of vitamin A, retinoic acid (RA), is required for proper brain formation and neurogenesis, but its precise role in eye development remains unclear. Proper eye morphogenesis requires a tight coordination of complex morphogenetic movements and precise spatial and temporal gene expression. Mutations in RA synthesis enzyme, aldehyde dehydrogenase 1a3 (aldh1a3), are associated with human MAC cases. We hypothesize that retinoic acid synthesized in the dorsal and ventral retina is required for proper eye morphology and proper optic fissure closure. To test this hypothesis, we used a combinatorial approach to block RA synthesizing enzymes thereby reducing endogenous levels of RA during embryogenesis. To achieve this, we depleted three RA synthesis enzymes that are expressed within dorsal and/or ventral domains of the retina: aldehyde dehydrogenase 1a2 (aldh1a2), aldehyde dehydrogenase 1a3 (aldh1a3) and cytochrome p450 1b1 (cyp1b1). We studied the function of RA using zebrafish, a genetically tractable model vertebrate whose transparent embryogenesis and external fertilization enables observation of eye development. Our studies revealed that RA is required for the closure of the optic fissure and may be implicated in the regulation of eye size. However, RA signalling is not required for dorsoventral retinal patterning. Interestingly, we observed that RA synthesized within the ventral retina signals within the dorsal retina. The vertebrate retina is a highly organized and laminar structure, the development of which is conserved among all vertebrates. Differentiation of retinal cell types from retinal progenitor cells is influenced by extrinsic and intrinsic factors. Previous studies have shown that sustained high levels of RA influences retinal cell fate decision. To better understand how RA synthesized in the retina is required for retinal neurogenesis, we used depleted RA synthesis enzymes to reduce endogenous RA levels. We observed a depletion of RA levels results in a reduction of rod photoreceptors. Further, we have obtained preliminary data that suggests that RA levels influence cone photoreceptor fate, biasing towards the differentiation of blue- and ultraviolet (UV)-sensitive cones. Taken together, we observed that RA plays a role both in eye morphogenesis as well as retinal neurogenesis. This analysis is paving the way to understanding how mutations in RA-synthesizing enzymes are causing ocular pathologies.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Laura M. Pillay, Lyndsay G. Selland, Valerie C. Fleisch, Patricia L. A. Leighton, Caroline S. Cheng, Jakub K. Famulski, R. Gary Ritzel, Lindsey D. March, Hao Wang, W. Ted Allison, and Andrew J. Waskiewicz. 2013. Evaluating the mutagenic activity of targeted endonuclease containing a Sharkey FokI cleavage domain variant in zebrafish. Zebrafish. 10(3):353-364.

File Details

Date Uploaded
Date Modified
Audit Status
Audits have not yet been run on this file.
File format: pdf (PDF/A)
Mime type: application/pdf
File size: 8207918
Last modified: 2016:06:16 16:56:57-06:00
Filename: Cheng_Caroline_ST_201601_PhD.pdf
Original checksum: 9c7a7ae83de2fd041602e3e65d8d91d9
Activity of users you follow
User Activity Date