Date Available

4-15-2021

Year of Publication

2021

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Biology

Advisor

Dr. Jakub Famulski

Abstract

The vertebrate eye is a complex organ, responsible for the primary sense with which we interact with our environment: vision. Development of the eye is a tightly regulated process, controlled by a vast network of genes. This process begins with eye morphogenesis, when the eye structure is formed through a series of morphogenetic movements and culminates in the creation of the optic cup, lens, and presumptive optic stalk. Next, retinal differentiation creates the critical cell layers of the retina needed to process light waves that enter the eye, including rod and cone photoreceptors, interneurons, and support cells. Failure in either one of these steps can result in developmental congenital defects or disorders which can range from relatively minor visual impairment to blindness. While extensive research has already been done to understand congenital blinding disorders, we have only begun to scratch the surface of understanding key parts of eye development and the intrinsic and extrinsic factors that go into regulating the process. While many researchers focus their work on eye morphogenesis or retinal differentiation in relation to these disorders, little attention is given to a process that overlaps with both stages: formation of the anterior segment (AS). The AS is a collection of individual structures located in the front third of the eye and has different developmental origins from the rest of the eye. AS structures are formed from a specialized group of neural crest-derived cells called Periocular Mesenchyme (POM) cells, which migrate around the forming optic cup to colonize the space between the anterior most regions of the optic cup and the surface ectoderm. Once positioned in this space, POM cells will specify into their cell types and form structures that include the corneal stroma and endothelium, the iris and ciliary body, and drainage network of the iridocorneal angle. Failure in the migration or specification of these cells can result in Anterior Segment Dysgenesis and a spectrum of visual impairment. Presently, little is understood about this transient cell population, its origins within the neural crest, its migration to the AS, or its genetic makeup during colonization and differentiation of the AS. In this dissertation, I examine in detail the POM cell population in zebrafish, focusing on its heterogeneity as well as its origins within the neural crest. In Chapter 3, I utilize several transgenic lines for POM-related transcription factors to demonstrate the heterogeneity of the POM through distribution mapping, co-expression analysis, migration behavior, and single cell RNA sequencing. I provide the first large scale evidence that the POM is a collection of subpopulations working in conjunction with one another to form the AS. In Chapter 4 I outline the role of the neural crest in POM formation and the consequences that loss of neural crest has on the development of the POM, as well as the AS. My findings provide a new lens with which to understand AS development and the cells responsible for it, and ultimately uncover new pathways for understanding the biological mechanisms involved in Anterior Segment Dysgenesis and AS-related blinding disorders.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.047

Funding Information

This research was supported by the National Institutes of Health Research Project Grant (R01 EY027805) from 2018-2022 and the Knights Templar Eye Foundation Career Starter Grant in 2016.

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