INVESTIGATING THE ROLE OF CHD7 AND SOX11 IN RETINAL CELL DEVELOPMENT AND THE OCULAR COMPLICATIONS OF CHARGE SYNDROME
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Year of Publication
Doctor of Philosophy (PhD)
Arts and Sciences
Dr. Ann C. Morris
Proper formation of the visual system requires the precise interaction of several embryonic cell lineages, including the neuroectoderm (forms the retina and retinal pigment epithelium), surface ectoderm (forms the lens), mesoderm and cranial neural crest cells (form the ocular blood vessels and anterior ocular structures). When this process is disrupted structural birth defects such as coloboma result, leading to pediatric visual deficits. Ocular developmental defects are often present in larger syndromic disorders. One example is CHARGE syndrome, a genetic disorder characterized by coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Pathogenic variants in CHD7 have been identified as the most common genetic cause of CHARGE syndrome, however the mechanistic details of how these pathogenic variants result in ocular defects are poorly understood. Further work is needed to understand the developmental pathways that control oculogenesis and retinal neurogenesis, and to uncover the mechanism leading to the clinical phenotypes observed in CHARGE.
This work focuses on investigating and developing tools to better understand the function of Chd7 and Sox11 in retinal development and photoreceptor maintenance, and how loss of expression causes the ocular phenotypes observed in CHARGE syndrome. The neural retina is formed from the inner layer of the optic cup, and the single pool of retinal progenitor cells ultimately differentiates into six different neuronal classes and the Müller glia. The different retinal cell types are generated in a conserved temporal order and lead to construction of the structures allowing for phototransduction. CHD7, a member of the CHD family of ATP-dependent chromatin remodelers, has been shown to have a role in neurogenesis in several different areas of the nervous system including the brain, spinal cord, auditory, and olfactory structures; however, little is known about its role in retinal development. The second gene of interest, Sox11, is a member of the SoxC family of transcription factors and has been shown to be a downstream target of CHD7 in brain neurogenesis. Knockdown of Sox11 in zebrafish results in microphthalmia, coloboma, brain, trunk, and heart defects, all phenotypes observed in CHARGE syndrome. However, the connection between Chd7 and Sox11 in retinal development is still relatively unexplored.
Chapter 1 of this dissertation is a review of eye development with a focus on retinal development, the ocular defects of CHARGE syndrome, and what is known about the functions of Chd7 and Sox11. Chapter 2 focuses on characterizing the expression of Chd7 in the developing retina of two animal models. Using two different mutant zebrafish lines for Chd7, this work demonstrates that there is a role for Chd7 in retinal neurogenesis and uncovers a novel role for Chd7 in photoreceptor maintenance. Chapter 3 describes the development of a transgenic zebrafish line in which Sox11a carries an in-frame epitope tag, which will allow for further study of Sox11a expression and provides a tool for identification of its transcriptional targets. Chapter 4 describes the process to establish mutant lines for both co-orthologues of Sox11, sox11a and sox11b, and the beginning characterization of retinal phenotypes in sox11 mutants. Chapter 5 is a discussion of conclusions from these studies and how these findings lead to future work connecting Chd7 and Sox11 with retinal development and CHARGE syndrome.
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This study was supported by the National Institute of Health and National Eye Institute (F30EY031545, 2021-Present), the CHARGE Syndrome Foundation (2019), the Center for Clinical and Translational Science TL1 Fellowship (2019-2021).
Krueger, Laura, "INVESTIGATING THE ROLE OF CHD7 AND SOX11 IN RETINAL CELL DEVELOPMENT AND THE OCULAR COMPLICATIONS OF CHARGE SYNDROME" (2022). Theses and Dissertations--Biology. 85.