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Gsx Genes Control the Neuronal to Glial Fate Switch in Telencephalic

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Gsx Genes Control the Neuronal to Glial Fate Switch in Telencephalic Gsx genes control the neuronal to glial fate switch in telencephalic progenitors A dissertation submitted to the Division of Research and Advanced studies of the University of Cincinnati In partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) In the Program of Molecular and Developmental Biology of the College of Medicine 2013 by Heather M. Chapman B.S., The Ohio State University, 2007 Committee Chair: Kenneth Campbell, Ph.D. Nadean Brown, Ph.D. Brian Gebelein, Ph.D. Masato Nakafuku, M.D., Ph.D. Ronald Waclaw, Ph.D. John MacLennan, Ph.D. ABSTRACT During development of the telencephalon, neurons and glia (oligodendrocytes and astrocytes) are sequentially generated in a precise temporal and spatial manner. Neurogenesis first occurs in early neural progenitors and is followed by a fate switch to gliogenesis at mid-late stages of embryogenesis, which leads to subsequent production of predominately oligodendrocytes and astrocytes (Bayer and Altman, 1991). The neuronal to oligodendroglial switch occurs in a ventral-to-dorsal manner, and likely involves repressive mechanisms during the neurogenic phase to prevent precocious specification of OPCs. The molecular mechanisms involved in regulating this fate switch in early telencephalic progenitors have not been completely elucidated. In the lateral ganglionic eminence (LGE), a sub-region of the ventral telencephalon, the homeobox gene Gsx2 is expressed within early ventricular zone (VZ) progenitors and is required for the specification of neuronal subtypes from this region. However, the role of Gsx2 in the generation of glial lineages remains unknown. The primary aim of this dissertation is to establish the role of Gsx2, and closely related gene Gsx1, in oligodendroglial specification, potentially elucidating novel mechanisms that assist in regulation of the timing of the neuronal to glial transition in telencephalic progenitors. Using various knockout and over-expression mouse models, Gsx2 has been shown to regulate the timing of OPC production from dLGE progenitors. This likely occurs through promotion of downstream neuronal factors to bias progenitors towards neurogenesis. Because of this repressive effect of Gsx2 on oligodendroglia specification, only after its down-regulation can OPC specification from these progenitors proceed. These increased OPCs require Ascl1 to expand into adjacent mantle regions (e.g. cortex). Thus, Gsx2 appears to limit oligodendrogenesis during neurogenic periods, thus regulating the timing and number of OPCs ii generated from LGE progenitors. Furthermore, analysis of Gsx1/2 double mutants indicate that in addition to promoting LGE neuronal subtypes, Gsx1 is also able to inhibit specification of OPCs from LGE progenitors, mimicking the activity of Gsx2. Thus, Gsx1 has a compensatory role in the absence of Gsx2, and is able to partially restore neurogenesis and repress precocious oligodendroglial specification from the dLGE. Furthermore, Gsx1 is also required for the subsequent expansion of these LGE-derived OPCs. iii iv ACKNOWLEDGEMENTS I would like to thank my advisor, Kenny Campbell, for all of his guidance throughout the course of my graduate career. I am very grateful for all of the experiences I have gained during my time under his supervision. I admire his vast scientific knowledge and also his enthusiasm for science as well as his students. He has helped me grow tremendously over the past six years, not only in my ways of scientific thinking, but also in my self-confidence. I appreciate all of his time, patience, and encouragement in helping me develop as a graduate student. I am also very grateful to my committee members, Masato Nakafuku, Ron Waclaw, Nadean Brown, Brian Gebelein, and John Maclennan for their guidance and very helpful suggestions on my thesis projects throughout my graduate career. I also would like to thank all of the current and previous members of the Campbell lab for all of their ongoing support and friendship. I would like to give a special thanks to Ron Waclaw for my initial technical training in the lab as well as all of his help and guidance with ongoing projects and collaborations. I would also like to thank Zhenglei Pei for her advice and help with Gsx2 over-expression studies. I appreciate all of the advice, friendship, and overwhelming support of all of the current lab members, including Paloma Merchan-Sala, Shenyue Qin, Kaushik Roychoudhury, and Jeff Kuerbitz. Next, I would also like to acknowledge Mayur Madhavan, Zegary Allen, Lisa Ehrman, and Ilya Vilinski for all the great experiences and time shared in the lab. Furthermore, I thank Amy Riesenberg, Carli Calderone, Sarah Ehrman, and Claire Schreiner for all of their technical assistance in the lab. I would also like to thank the Enhanced Training Opportunities program and Dr. Rashmi Hegde for the opportunity to pursue an internship in clinical genetics. In addition, I would like v to give great thanks to Kejian Zhang and Alex Valencia for all of the training and guidance and for providing invaluable experiences during my internship. Last, but not least, I would like to thank all of my family and friends for their support and encouragement over the past six years. I would like to give a special thanks to my mom and dad for all of their unwavering support and love and pushing me to always pursue my dreams. Also a special thanks to my brother, Brian, for all of his encouragement and love and helping me stay positive through trying times. Thank you, I am very grateful for the time I have been able to share with everyone. vi TABLE OF CONTENTS ABSTRACT……………………………………………………………………………………..ii ACKNOWLEDGEMENTS…………………………………………………………………….iv TABLE OF CONTENTS…………………………………………………………………….....vi CHAPTER 1. Introduction Overview………………………………………………………………………………………….2 General telencephalon development and organization.......................................................……...2 Molecular identities of the LGE and MGE………………………………………………..………4 Genomic Screen Homeobox genes……………………………………………………………….5 Gsx genes and neurogenesis within the developing telencephalon………………………………6 Oligodendrocyte specification within the developing telencephalon…………………………….8 Summary…………………………………………………………………………………………11 References………………………………………………………………………………………..13 Figures and Legends……………………………………………………………………………..22 CHAPTER 2. The homeobox gene Gsx2 controls the timing of oligodendroglial fate specification in mouse lateral ganglionic eminence progenitors……………………..……..25 Summary…………………………………………………………………………………………26 Introduction………………………………………………………………………………………27 Materials and Methods…………………………………………………………………………...30 Results……………………………………………………………………………………………33 Discussion………………………………………………………………………………………..43 vii References……………………………………………………………………………………….50 Figures and Legends…………………………………………………………………………..…57 CHAPTER 3. Gsx1 negatively regulates specification of LGE-derived OPCs but is required for their full expansion potential in the Gsx2 mutant telencephalon………………………..70 Summary…………………………………………………………………………………………71 Introduction………………………………………………………………………………………72 Materials and Methods…………………………………………………………………………...75 Results……………………………………………………………………………………………78 Discussion………………………………………………………………………………………..86 Reference………………………………………………………………………………………...90 Figures and Legends…………………………………………………………………………..…93 Chapter 4. General Discussion………………………………………………………………..102 Overview………………………………………………………………………………………..103 Gsx2 regulates the neuronal to oligodendroglial switch through downstream effectors….........103 High levels of Gsx2 are able to inhibit OPCs likely through promotion of downstream genes ………………………………………...……………………………………105 The role of Gsx1 in oligodendroglial specification…………………………………….………106 The role of Gsx1 versus Ascl1 in the absence of Gsx2………………………………….……..109 Generation of OPCs in MGE versus LGE…………………………………………….………..111 Heterogeneity of Gsx2-expressing progenitors………………………………………………...112 Gsx genes and retinoic acid signaling…………………………………………………………..113 viii Potential interactions with Gsx genes……………………………………………………..……115 Gsx genes and astrogliogenesis…………………………………………………………...……117 Gsx genes and adult neurogenesis…………………………………………………………...…119 Gsx genes and medical implications……………………………………………………………121 References………………………………………………………………………………………124 Figures and Legends……………………………………………………………………………131 ix CHAPTER 1 Introduction 1 Overview In central nervous system (CNS) development, neural stem cell lineages are generated in precise temporal and spatial manners. Progenitors initially give rise to neurons, however at later stages of embryogenesis there is a neuronal to glial fate switch, which leads to subsequent generation of predominately oligodendrocytes and astrocytes (Bayer and Altman, 1991). The molecular mechanisms that control this transition in early telencephalic progenitors are not fully understood. In a sub-region of the ventral telencephalon, the lateral ganglionic eminence (LGE), the homeobox gene Gsx2 is expressed within early neural progenitors and promotes the specification of neuronal subtypes from this region. Whether Gsx2 has any effect on the specification of glial lineages remains unknown. The primary goal of this dissertation is to understand the role of Gsx2, and closely related gene Gsx1, in oligodendroglial specification, thereby potentially elucidating mechanisms that assist to regulate the timing of the neuronal to glial fate switch in telencephalic progenitors. General telencephalon development and organization During development, the
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