The role of Lsd1 in the development of the retina and retinoblastoma Open Access
Ferdous, Salma (Spring 2021)
Abstract
The increasing importance of epigenetics on neuronal developmental and diseases, also known as “neuroepigenetics” is becoming widely recognized. Neurological abnormalities are frequently associated with many Mendelian disorders related to the epigenetic machinery, indicating that neurons may be uniquely sensitive to epigenetic dysregulation. Lysine specific demethylase 1 (Lsd1), also known as Kdm1A, was the first histone demethylase to be discovered. Through interactions with other proteins, Lsd1 is able to demethylate H3K4, H3K9, and H4K20 as well as other non-histone proteins, such as p53. Lsd1 is known to be important in neuronal development, particularly due to a neuron-specific isoform, neuro Lsd1 (nLsd1). Lsd1 overexpression is observed in many different cancers and the development of Lsd1inhibitors has become a promising new research area. Although Lsd1 has been extensively studied in brain development and disease, there is relatively little known about its role in the visual system, particularly in the retina. The purpose of this study was to increase our understanding of the role of Lsd1 in retinal development and determine whether Lsd1 may be a viable therapeutic target in retinoblastoma, a pediatric ocular cancer. Using transgenic mouse models and human retinoblastoma samples, we determined the normal expression of Lsd1 during and after murine retina development. We found that Lsd1 is expressed in all retinal progenitor cells (RPCs) and has peak expression at post-natal 7 (P7). Afterwards, expression decreases until reaching a maintenance basement level at post-natal day 36 (P36). Lsd1 has variable expression in the adult mouse retina in different mature retinal neuronal types. Based on these results, we explored how the deletion of Lsd1 would affect proper retinal development in transgenic mice. Although heterozygous Lsd1 mice do not show any visual abnormalities, homozygous deletion of Lsd1 in RPCs results in severe retinal degeneration, causing significant decreases in visual function and defects in retinal morphology. Lastly, we investigated the expression pattern of Lsd1 in human and mouse retinoblastoma samples and found that Lsd1 is overexpressed in highly differentiated and proliferating tumor cells. Therefore, Lsd1 may be a potential molecular target for the development of new therapeutic options in retinoblastoma.
Table of Contents
Chapter I.
Introduction
1
Purpose and premise of this dissertation
2
Premise for Aim 1: The role of Lsd1 in normal retinal development
2
Premise of Aim 2: Lsd1 is a potential therapeutic target in retinoblastoma
2
Outline of the dissertation
3
References
4
Chapter II
The contribution of histone demethylases, specifically Lsd1, in the development of two neuronal tissues, the brain and the eye
7
Abstract
8
General epigenetics
9
Histone methylation
9
Lysine specific demethylase 1 (Lsd1)
11
Neuronal specific isoform of Lsd1 (nLsd1)
11
Consequences of Lsd1 deletion or dysregulation in both brain development and disease
12
Retinal development, structure, and function
14
The role of Lsd1 in the visual system - current knowledge and unanswered questions
15
References
21
Chapter III
Characterization of LSD1 expression within the murine eye
31
Abstract
32
Introduction
33
Methods
35
Results
42
Discussion
49
Figures & tables
50
References
73
Chapter IV
Pan-retinal deletion of Lsd1 during retinal development leads to visual function and morphological defects
81
Abstract
82
Introduction
83
Methods
86
Results
91
Discussion
94
Figures & tables
98
References
112
Chapter V
Lsd1 is a potential therapeutic target in the treatment of retinoblastoma
117
Abstract
118
Introduction
119
Methods
121
Results
123
Discussion
125
Figures & Tables
128
References
131
Chapter VI
Age-related ocular changes in wildtype C57Bl/6J mice between 2 and 32 months
132
Abstract
140
Introduction
143
Methods
144
Results
148
Discussion
151
Figures & tables
156
References
203
Chapter VII
Discussion
208
Summary
209
Future directions
212
Overall impact
216
References
219
About this Dissertation
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