Author ORCID Identifier
Date Available
8-20-2020
Year of Publication
2020
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Arts and Sciences
Department/School/Program
Biology
First Advisor
Dr. Jakub K. Famulski
Second Advisor
Dr. Robin L. Cooper
Abstract
The eye is a complex organ responsible for vision that which formation depends on several intricate developmental steps. Vision for humans is responsible for the majority of its sensory interactions with the environment. Eye development can be divided into two critical stages: morphogenesis, which establishes the eye structure culminating with the fusion of the optic fissure, a transient cleft important for eye vascularization, and subsequently specification and differentiation of the retina to form every type of retinal neuronal cell, including photoreceptors, rods and cones. Developmental failure in either of these critical stages can lead to inherited congenital or age-related blinding disorders. Thus, understanding the proper mechanism for eye development is crucial to help avoid social and cognitive impairments commonly associated with visual loss, especially in the most economically challenged parts of the world. The regulation of morphogenesis and retinal formation has been vigorously investigated at the transcriptional level, but little effort has been placed on potential post-translational regulatory mechanisms. The ubiquitin mediated proteasome degradation system plays an important role in regulating protein function in many different developmental stages. The siah family of ubiquitin E3 ligases are homologues to Drosophila Seven In Absentia (SINA), and also known regulators of drosophila photoreceptor development. In order to determine whether Siah mediated ubiquitin-targeting plays a role in vertebrate eye morphogenesis and retinal differentiation, the zebrafish proteome was screened for siah degron motifs and identified 2 potential targets related to eye development, Nlz2 and Cdhr1a. The first is a zinc-finger transcription factor, responsible for negatively regulating Pax2 gene expression, a master regulator of the optic fissure closure. The second, is a photoreceptor’ specific cadherin, known to be associated with cone-rod dystrophies. My dissertation has focused on examining Siah-mediated regulation of these two targets during critical stages of eye development. In Chapter 3 I outline how modulation of Siah activity leads to failure of optic fissure fusion dependent on ubiquitin-mediated proteasomal degradation of Nlz2, outlining a novel, UPS-mediated degradation regulatory pathway involved in optic fissure fusion. In Chapter 4 I provide the first evidence that Cdhr1a is involved in photoreceptor development and that Siah1 is responsible for regulating its protein stability via the UPS. My findings provide new avenues for investigation of the pathogenesis of inherited cone-rod dystrophies. Overall, my work outlines new pathways involved in posttranslational mechanisms of vertebrate retinal development and strengthens efforts to improve our understanding of the predisposition and pathogenesis of Coloboma and inherited cone-rod dystrophy.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2020.479
Funding Information
Supported by Brazilian National Council for Scientific and Technological Development (CNPq) under grant number 202970/2014-0. - August 2015 – July 2019
2017 Ribble Mini-grant - May 2017 – December 2017
2019 Ribble Mini-grant - May 2019 – December 2020
Morgan Graduate Fellowship - August 2019 – January 2020
Recommended Citation
Pereira Piedade, Warlen, "SIAH-MEDIATED UPS REGULATION OF THE DEVELOPMENT OF THE VISUAL SYSTEM IN ZEBRAFISH (DANIO RERIO)" (2020). Theses and Dissertations--Biology. 71.
https://uknowledge.uky.edu/biology_etds/71
